JP2009517383A - Novel 3-bicyclocarbonylaminopyridine-2-carboxamide or 3-bicyclocarbonylaminopyrazine-2-carboxamide - Google Patents

Abstract

The present invention relates to a compound of formula (I) (see the chemical formula below); where A ¹ , A ² , R ¹ , R ² , R ³ , R ⁴ and R ⁵ , and n are defined herein. As well as pharmaceutically acceptable salts thereof and compounds or salts thereof. The compounds of formula (I) are useful for therapy.
[Chemical 1]

Description

  The present invention relates to a novel compound, a pharmaceutical composition containing the compound, a production method and use thereof. The present invention also relates to compounds effective in the treatment of pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and / or cardiovascular disorders.

Cannabinoid receptor (eg, CB ₁ receptor, CB ₂ receptor) ligands, including agonists, antagonists and inverse agonists, interact with CB ₁ and / or CB ₂ receptors to cause pain in various animal models. It is known to reduce. In general, CB ₁ receptors are predominantly present in the central nervous system, whereas CB ₂ receptors are predominantly present in the peripheral part and are limited primarily to cells and tissues derived from the immune system.

Delta ⁹ - CB ₁ receptor agonists, such as tetrahydrocannabinol (Δ ⁹ -THC) and Anadamido are useful in animal antinociceptive models, they are, for example, psychoactive side effects, the abuse potential, There is a tendency to exert undesirable CNS side effects such as drug dependence and tolerance. These undesirable side effects are known to be mediated by the CB ₁ receptor present in the CNS. However, some evidence suggests that CB1 agonists acting at peripheral sites or acting on limited exposure CNS may be processed to improve the overall in vivo profile of pain in humans or animals There is.

  The lower esophageal sphincter (LES) tends to relax intermittently. As a result, the mechanical barrier is temporarily lost at such times, allowing passage of fluid from the stomach into the esophagus. Hereinafter, this phenomenon is referred to as “backflow”.

  Gastroesophageal reflux disease (GERD) is the most common upper gastrointestinal disease. Current drug therapy aims at reducing gastric acid secretion or acid neutralization in the esophagus. The main mechanism involved in reflux is thought to be due to the hypotonic lower esophageal sphincter. However, for example, in Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535, most reflux episodes occur during transient lower esophageal sphincter relaxation (TLESR), ie It indicates that relaxation is not induced by swallowing. It has also been shown that normal gastric acid secretion is normal in GERD patients. GERD occurs when the stomach contents flow back into the esophagus, causing heartburn and other typical symptoms. In many cases, inflammation (esophagitis) occurs in the lower part of the esophagus. It has long been known that suppression of gastric acid production improves both symptoms and esophagitis. However, some patients continue to have symptoms despite adequate control of acid secretion. Other adverse causes of reflux appear to be involved in these symptoms. Most focus is on the importance of bile acids, and the development of severe GERD is related to the degree to which the esophagus contacts bile acids.

There is a need for new CB ₁ receptor ligands, such as agonists that are useful in the treatment of gastrointestinal disorders or pain or in the treatment of other related conditions or diseases, with less or minimal undesirable CNS side effects Yes.

The present invention provides CB ₁ receptor ligands useful for the treatment of pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and / or cardiovascular disorders.

［式中、
Ａ¹及びＡ²の内の少なくとも１つはＮであり、両者がＮでない場合は他方はＣＨであり；
Ｒ¹は、水素、シアノ、ハロゲン、ヒドロキシ、ＮＲ⁶Ｒ⁷、Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、Ｃ_1-9アルキル、Ｃ_3-6シクロアルキル及びＣ_1-6ハロアルコキシから選択され；ここで、該Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、Ｃ_1-9アルキル、Ｃ_3-6シクロアルキル又はＣ_1-6ハロアルコキシは、場合により、ヒドロキシ、ＮＲ^6aＲ^7a、Ｃ_3-6シクロアルキル、アリール及びヘテロアリールで置換され；
Ｒ²は、水素、シアノ、ハロゲン、ヒドロキシ、ＮＲ⁶Ｒ⁷、Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル及びＣ_1-6ハロアルコキシから選択され；ここで、該Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル又はＣ_1-6ハロアルコキシは、場合により、ヒドロキシ、ＮＲ^6aＲ^7a、Ｃ_3-6シクロアルキル、アリール及びヘテロアリールで置換され；
Ｒ³は下記の基：

から選択され、ここで、Ｒ³は、場合により、ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール又はヘテロアリールで置換され；ここで、該Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、アリール又はヘテロアリールは、場合により、ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール、ヘテロアリール、又はＣ、Ｎ及びＯから選択される４〜７個の原子から成る飽和の環系で置換され；ここで、該Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、アリール、ヘテロアリール又は環系は、場合により、Ｃ_1-4アルキルで置換され；ここで、該Ｃ_1-4アルキルは、場合により、ＮＲ⁶Ｒ⁷、アリール、ヒドロキシ又はＣ_1-4アルコキシで置換され；
Ｒ⁴は、水素及びＣ_1-6アルキルから選択され；
Ｒ⁵は、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、ヘテロアリール及びアリールから選択され；ここで、該Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、ヘテロアリール又はアリールは、場合により、ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール又はヘテロアリールで置換され；
ｎは、０、１、２、３、４及び５から選択され；
又は、Ｒ⁴及びＲ⁵は一緒になり、Ｃ、Ｏ及びＮから選択される３〜７個の原子から成る飽和の、不飽和の、又は部分的に飽和の環系を形成し；
又は、Ｒ⁴及びＲ⁵は一緒になり、Ｃ、Ｏ及びＮから選択される７〜１３個の原子から成る飽和の、不飽和の、又は部分的に飽和の縮合環系を形成し；
ここで、該環系は、場合により、ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール又はヘテロアリールで置換され；ここで、該Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、アリール又はヘテロアリールは、場合により、ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール又はヘテロアリールにより置換され；
Ｒ⁶、Ｒ^6a、Ｒ⁷及びＲ^7aは、互いに独立に、水素、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、アリール及びヘテロアリールから選択され；又は
Ｒ^6a及びＲ^7aは一緒になり、Ｃ、Ｏ及びＮから選択される４〜７個の原子から成る飽和の環系を形成しても良く、そしてその環系は、場合により、Ｃ_1-6アルキル、Ｃ_1-6アルコキシ、ハロゲン又はヒドロキシで置換され；
ここで、Ｒ¹で定義されるアルキル又はシクロアルキルの１つ又はそれ以上の炭素原子は、Ｏ、ＮＨ、Ｃ（Ｏ）、ＳＯ又はＳＯ₂で置換されても良く；ここで、Ｎ又はＯのいずれも、別のＯ又はＮのいずれにも隣接せず；そして、ＳＯ又はＳＯ₂のいずれも、別のＳＯ又はＳＯ₂のいずれにも隣接せず；
ここで、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ^6a、Ｒ⁷及びＲ^7aで定義されるアルキル又はシクロアルキルの１つ又はそれ以上の炭素原子は、Ｏ、ＮＨ、Ｃ（Ｏ）又はＳＯ₂で置換されても良く；ここで、Ｎ又はＯのいずれも、別のＯ又はＮのいずれにも隣接せず；
ここで、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ^6a、Ｒ⁷及びＲ^7aで定義されるアルキル又はシクロアルキルの１つ又はそれ以上の炭素原子は、フッ素で置換されても良く；但し、
Ｒ³がＣ_1-4アルキル：ここで、Ｃ_1-4アルキルは、ヘテロアリール、Ｃ_3-6シクロアルキル、アリール、又はＣ、Ｏ及びＮから選択される４〜７個の原子から成る飽和の環系で置換され、ここで、該ヘテロアリール、Ｃ_3-6シクロアルキル又はアリールは、更に、Ｃ_1-4アルキル又はハロゲンで置換され、ここで、該Ｃ_1-4アルキルは、場合により、ＮＲ⁶Ｒ⁷、アリール、ヒドロキシ又はＣ_1-4アルコキシで置換され、ここで、該環系は、場合により、Ｃ_1-4アルキルで置換され、ここで、該Ｃ_1-4アルキルは、場合により、ＮＲ⁶Ｒ⁷、アリール、ヒドロキシ又はＣ_1-4アルコキシで置換される、で置換されない場合；
又は、Ｒ³が、下記の基：

ここで、Ｒ³は、場合により、ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール又はヘテロアリールで置換される：
から選択されない場合は、
Ｒ²が、水素、ハロゲン、シアノ、アセチルアミノ、ヒドロキシ、Ｃ_1-6アルコキシ、Ｃ_1-6アルキル、Ｃ_1-6ハロアルコキシ、Ｃ_2-6アルケニル、Ｃ_1-6ハロアルキル、Ｃ_2-6ハロアルケニル又はＮＲ⁶Ｒ⁷の場合、同時にＲ¹が、水素、ハロゲン、シアノ、アセチルアミノ、ヒドロキシ、Ｃ_1-6アルコキシ、Ｃ_1-6アルキル、Ｃ_1-6ハロアルコキシ、Ｃ_2-6アルケニル、Ｃ_1-6ハロアルキル、Ｃ_2-6ハロアルケニル又はＮＲ⁶Ｒ⁷であることはない］
の化合物、又は薬学的に許容されるその塩、ジアステレオマー、エナンチオマー、若しくはその混合物に関する。 The present invention relates to a compound of formula (I):

[Where:
At least one of A ¹ and A ² is N, and if both are not N, the other is CH;
R ¹ is selected from hydrogen, cyano, halogen, hydroxy, NR ⁶ R ⁷ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-9 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy Wherein the C _2-6 alkenyl, C _2-6 alkynyl, C _1-9 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkoxy is optionally hydroxy, NR ^6a R ^7a , C Substituted with _3-6 cycloalkyl, aryl and heteroaryl;
R ² is selected from hydrogen, cyano, halogen, hydroxy, NR ⁶ R ⁷ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy Wherein the C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkoxy is optionally hydroxy, NR ^6a R ^7a , C Substituted with _3-6 cycloalkyl, aryl and heteroaryl;
R ³ is the following group:

Wherein R ³ is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy Wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 In saturated ring systems consisting of 4 to 7 atoms selected from alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl, heteroaryl, or C, N and O Wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl or ring system is optionally substituted with C _1-4 alkyl; wherein the C _1-4 alkyl Is optionally NR ⁶ R ⁷ , aryl, Substituted with hydroxy or C _1-4 alkoxy;
R ⁴ is selected from hydrogen and C _1-6 alkyl;
R ⁵ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, heteroaryl and aryl; wherein the C _1-6 alkyl, C _{3 -6} cycloalkyl, heteroaryl or aryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy Substituted with aryl or heteroaryl;
n is selected from 0, 1, 2, 3, 4 and 5;
Or R ⁴ and R ⁵ together form a saturated, unsaturated or partially saturated ring system of 3 to 7 atoms selected from C, O and N;
Or R ⁴ and R ⁵ together form a saturated, unsaturated or partially saturated fused ring system of 7 to 13 atoms selected from C, O and N;
Wherein the ring system is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or Substituted with heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C Substituted by _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or heteroaryl;
R ⁶ , R ^6a , R ⁷ and R ^7a are independently of each other hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl. , C _2-6 alkynyl, aryl and heteroaryl; or R ^6a and R ^7a together form a saturated ring system of 4-7 atoms selected from C, O and N. And the ring system is optionally substituted with C _1-6 alkyl, C _1-6 alkoxy, halogen or hydroxy;
Wherein one or more carbon atoms of the alkyl or cycloalkyl defined by R ¹ may be substituted with O, NH, C (O), SO or SO ₂ ; where N or O both not adjacent to any other O or N in; and none of the SO or SO _2, not adjacent to any other SO or SO _2;
Here, one or more carbon atoms of alkyl or cycloalkyl defined by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ⁷ and R ^7a are O, NH, C May be substituted with (O) or SO ₂ ; where N or O is not adjacent to any other O or N;
Wherein one or more carbon atoms of alkyl or cycloalkyl as defined by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ⁷ and R ^7a are fluorine May be substituted; provided that
R ³ is C _1-4 alkyl: wherein C _1-4 alkyl is heteroaryl, C _3-6 cycloalkyl, aryl, or saturated consisting of 4-7 atoms selected from C, O and N Wherein the heteroaryl, C _3-6 cycloalkyl or aryl is further substituted with C _1-4 alkyl or halogen, wherein the C _1-4 alkyl is optionally , NR ⁶ R ^7, aryl, substituted with hydroxy or C _1-4 alkoxy, wherein said ring system is optionally substituted by C _1-4 alkyl, wherein said C _1-4 alkyl, Optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy;
Or, R ³ is the following group:

Wherein R ³ is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or hetero Substituted with aryl:
If not selected from
R ² is hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _1-6 haloalkyl, C _2-6 In the case of haloalkenyl or NR ⁶ R ⁷ , R ¹ is simultaneously hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy, C _2-6 alkenyl , C _1-6 haloalkyl, C _2-6 haloalkenyl, or NR ⁶ R ⁷ ]
Or a pharmaceutically acceptable salt, diastereomer, enantiomer or mixture thereof.

［式中、
Ａ¹及びＡ²の内の少なくとも１つはＮであり、両者がＮでない場合は他方はＣＨであり；
Ｒ¹は、水素、シアノ、ハロゲン、ヒドロキシ、ＮＲ⁶Ｒ⁷、Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル及びＣ_1-6ハロアルコキシから選択され；ここで、該Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル又はＣ_1-6ハロアルコキシは、場合により、ヒドロキシ、ＮＲ^6aＲ^7a、Ｃ_3-6シクロアルキル、アリール又はヘテロアリールで置換され；
Ｒ²は、水素、シアノ、ハロゲン、ヒドロキシ、ＮＲ⁶Ｒ⁷、Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル及びＣ_1-6ハロアルコキシから選択され；ここで、該Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル又はＣ_1-6ハロアルコキシは、場合により、ヒドロキシ、ＮＲ^6aＲ^7a、Ｃ_3-6シクロアルキル、アリール又はヘテロアリールで置換され；
Ｒ³は、下記の基：

から選択され、ここで、Ｒ³は、場合により、ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール又はヘテロアリールで置換され；ここで、該Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、アリール又はヘテロアリールは、場合により、ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール又はヘテロアリールで置換され；ここで該Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、アリール又はヘテロアリールは、場合により、Ｃ_1-4アルキルで置換され；ここで、該Ｃ_1-4アルキルは、場合により、ＮＲ⁶Ｒ⁷、アリール、ヒドロキシ又はＣ_1-4アルコキシで置換され；
Ｒ⁴は、水素及びＣ_1-6アルキルから選択され；
Ｒ⁵は、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、ヘテロアリール及びアリールから選択され；ここで、該Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、ヘテロアリール又はアリールは、場合により、 ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール又はヘテロアリールで置換され；
ｎは、０、１、２、３、４及び５から選択され；
又は、Ｒ⁴及びＲ⁵は一緒になり、Ｃ、Ｏ及びＮから選択される３〜７個から成る飽和の、不飽和の、又は部分飽和の環系を形成し；
又は、Ｒ⁴及びＲ⁵は一緒になり、Ｃ、Ｏ及びＮから選択される７〜１３個から成る飽和の、不飽和の、又は部分飽和の縮合環系を形成し；
ここで、該環系は、場合により、ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、 アリール又はヘテロアリールで置換され；そして、ここで、該Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、アリール又はヘテロアリールは、場合により、ハロゲン、 シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール又はヘテロアリールで置換され；
Ｒ⁶、Ｒ^6a、Ｒ⁷及びＲ^7aは、互いに独立に、水素、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、Ｃ_2-6アルケニル、Ｃ_2-6アルキニル、アリール及びヘテロアリールから選択され；
ここで、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ^6a、Ｒ⁷及びＲ^7aで定義されるアルキル又はシクロアルキル基の１つ又はそれ以上の炭素原子は、Ｏ、ＮＨ、Ｃ（Ｏ）又はＳＯ₂で
置換されても良く；
ここで、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｒ⁶、Ｒ^6a、Ｒ⁷及びＲ^7aで定義されるアルキル又はシクロアルキル基の１つ又はそれ以上の炭素原子は、フッ素で置換されても良く；そして
Ｒ³が、Ｃ_1-4アルキル：ここで、Ｃ_1-4アルキルは、ヘテロアリール、Ｃ_3-6シクロアルキル又はアリールで置換され、それは更にＣ_1-4アルキルで置換され、ここで、該Ｃ_1-4アルキルは、場合により、ＮＲ⁶Ｒ⁷、アリール、ヒドロキシ又はＣ_1-4アルコキシで置換される、で置換されない場合；
又は、Ｒ³が、下記の基：

から選択されない場合は、
Ｒ²が、水素、ハロゲン、シアノ、アセチルアミノ、ヒドロキシ、Ｃ_1-6アルコキシ、Ｃ_1-6アルキル、Ｃ_1-6ハロアルコキシ、Ｃ_2-6アルケニル、Ｃ_1-6ハロアルキル、Ｃ_2-6ハロアルケニル又はＮＲ⁶Ｒ⁷の場合、同時にＲ¹が、水素、ハロゲン、シアノ、アセチルアミノ、ヒドロキシ、Ｃ_1-6アルコキシ、Ｃ_1-6アルキル、Ｃ_1-6ハロアルコキシ、Ｃ_2-6アルケニル、Ｃ_1-6ハロアルキル、Ｃ_2-6ハロアルケニル又はＮＲ⁶Ｒ⁷であることはない］
の化合物、又は薬学的に許容されるその塩、ジアステレオマー、エナンチオマー、若しくはその混合物に関する。 The present invention also provides a compound of formula (I):

[Where:
At least one of A ¹ and A ² is N, and if both are not N, the other is CH;
R ¹ is selected from hydrogen, cyano, halogen, hydroxy, NR ⁶ R ⁷ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy Wherein the C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkoxy is optionally hydroxy, NR ^6a R ^7a , C Substituted with _3-6 cycloalkyl, aryl or heteroaryl;
R ² is selected from hydrogen, cyano, halogen, hydroxy, NR ⁶ R ⁷ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy Wherein the C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkoxy is optionally hydroxy, NR ^6a R ^7a , C Substituted with _3-6 cycloalkyl, aryl or heteroaryl;
R ³ represents the following group:

Wherein R ³ is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy Wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 Substituted with alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or heteroaryl; wherein said C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl Is optionally substituted with C _1-4 alkyl; wherein the C _1-4 alkyl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy;
R ⁴ is selected from hydrogen and C _1-6 alkyl;
R ⁵ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, heteroaryl and aryl; wherein the C _1-6 alkyl, C _{3 -6} cycloalkyl, heteroaryl or aryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy Substituted with aryl or heteroaryl;
n is selected from 0, 1, 2, 3, 4 and 5;
Or, R ⁴ and R ⁵ come together, C, saturated consisting 3-7 groups selected from O and N, unsaturated, or partially saturated ring system;
Or R ⁴ and R ⁵ together form a 7-13 saturated, unsaturated or partially saturated fused ring system selected from C, O and N;
Wherein the ring system is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or Substituted with heteroaryl; and wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl Substituted with C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or heteroaryl;
R ⁶ , R ^6a , R ⁷ and R ^7a are independently of each other hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl. , C _2-6 alkynyl, aryl and heteroaryl;
Here, one or more carbon atoms of the alkyl or cycloalkyl group defined by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ⁷ and R ^7a are O , NH, C (O) or SO ₂ may be substituted;
Here, one or more carbon atoms of the alkyl or cycloalkyl group defined by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ⁷ and R ^7a are fluorine And R ³ is C _1-4 alkyl: wherein C _1-4 alkyl is substituted with heteroaryl, C _3-6 cycloalkyl or aryl, which is further C _1-4 alkyl When the C _1-4 alkyl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy;
Or, R ³ is the following group:

If not selected from
R ² is hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _1-6 haloalkyl, C _2-6 In the case of haloalkenyl or NR ⁶ R ⁷ , R ¹ is simultaneously hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy, C _2-6 alkenyl , C _1-6 haloalkyl, C _2-6 haloalkenyl, or NR ⁶ R ⁷ ]
Or a pharmaceutically acceptable salt, diastereomer, enantiomer or mixture thereof.

  Unless specified otherwise herein, the nomenclature used herein is generally the Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Following the examples and rules described in Oxford, 1979, which is incorporated herein by reference. The IUPAC nomenclature was obtained from ACD / Labs Name (version 9.04 2005).

The term “C _mn ” or “C _mn group” used alone or as a prefix, refers to a group having m to n carbon atoms.

The term “C _1-9 alkyl” includes straight or branched C _1-9 alkyl. Examples of C _1-9 alkyl include methyl, ethyl, propyl, n-propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, hexyl, octyl, nonyl and decyl. It is not limited.

The term “C _1-6 alkyl” includes straight or branched C _1-6 alkyl. Examples of C _1-9 alkyl include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl and hexyl.

The term “C _1-4 alkyl” includes straight or branched C _1-4 alkyl. Examples of C _1-4 alkyl include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl and hexyl.

The term “C ₃ -C ₆ cycloalkyl” is intended to include monovalent rings having 3 to 6 carbons. Examples of such rings are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “C _1-6 alkoxy” includes linear or branched C _1-6 alkoxy. Examples of C _1-6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propanoxy, isopropanoxy, isobutoxy, secondary butoxy and hexoxy.

The term “C _1-4 alkoxy” includes straight or branched C _1-4 alkoxy. Examples of C _1-4 alkoxy include, but are not limited to, methoxy, ethoxy, n-propanoxy, isopropanoxy, isobutoxy and secondary butoxy.

  The term “aryl” means an aromatic ring having from 6 to 14 carbons, including both monocyclic and polycyclic compounds. Examples of such rings include, but are not limited to, phenyl, benzyl and naphthyl.

  The term “heteroaryl” as used herein refers to a heteroaromatic ring having from 3 to 14 carbon atoms, wherein one or more ring atoms are oxygen or nitrogen or sulfur. Any, including monocyclic and polycyclic compounds. For example, a 5-membered heteroaryl is a heteroaryl with a ring having 5 ring atoms, wherein 1, 2 or 3 ring atoms are independently selected from N, O and S The Typical 5-membered heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2 , 3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4 -Oxadiazolyl. A 6-membered heteroaryl is a heteroaryl with a ring having 6 ring atoms, wherein 1, 2 or 3 ring atoms are independently selected from N, O and S. Exemplary 6-membered heteroaryls include pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “C _2-6 alkenyl” as used herein is a monovalent straight or branched chain having at least one carbon-carbon double bond and containing at least 2 to 6 carbon atoms. It is intended to refer to a branched hydrocarbon group.

The term “C _2-6 alkynyl” as used herein is a monovalent straight or branched chain having at least one carbon-carbon triple bond and containing at least 2 to 6 carbon atoms. It is intended to refer to a chain hydrocarbon group.

  The term “halogen” as used herein is intended to include fluorine, bromine and iodine.

  The term “halo” as used herein as a prefix means that one or more hydrogen atoms of a group are replaced with one or more halogens.

The term “nitro” as used herein is intended to refer to a NO ₂ — group.

In this application, the following abbreviations are used:
Acetylamino CH ₃ CONH;
Ar aryl;
CH ₂ Cl ₂ dichloromethane;
CH ₃ COOH acetic acid;
CH ₃ CN acetonitrile;
CHCl ₃ trichloromethane;
CCl ₄ tetrachloromethane;
DCM dichloromethane;
DIPEA N, N-diisopropylethylamine;
DMAP 4-dimethylaminopyridine;
DMF dimethylformamide;
EDTA ethylenediaminetetraacetic acid;
Et ₃ N triethylamine;
EtOAc ethyl acetate;
EtOH ethanol;
KCN potassium cyanide;
K ₂ CO ₃ potassium carbonate;
HCl hydrochloric acid;
MeOH methanol;
MeCN acetonitrile;
MgSO ₄ magnesium sulfate;
MTBE methyl tert-butyl ether;
NBS N-bromosuccinimide;
NaH sodium hydride;
NH ₄ Cl ammonium chloride;
NaOH sodium hydroxide;
NaHCO ₃ sodium bicarbonate;
Na ₂ SO ₄ sodium sulfate;
Pd (AcO) ₂ palladium diacetate;
Pd / C palladium on carbon;
RT room temperature;
TBTU benzotriazol-1-yl-N-tetramethyl-uronium tetrafluoroborate;
TFA trifluoroacetic acid;
TMEDA N, N, N ′, N′-tetramethyl-1,2-ethanediamine TMSCl trimethylsilyl chloride.

In one embodiment of the invention, A ¹ and A ² are N. According to another embodiment of the present invention, A ¹ is N and A ² is CH.

In another embodiment of the present invention, R ⁴ is hydrogen.

  In yet another embodiment of the invention n is 1.

In yet another embodiment of the present invention, R ² is hydrogen.

According to another embodiment of the present invention, R ² is C _1-6 alkyl optionally substituted with hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or heteroaryl.

In yet another embodiment of the present invention, R ¹ is hydrogen.

In yet another embodiment of the invention, R ¹ is selected from cyano, halogen, NR ⁶ R ⁷ , C _1-9 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy, wherein The C _1-9 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkoxy is optionally substituted with hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or heteroaryl.

According to another embodiment of the present invention, R ¹ is selected from cyano, halogen, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy, wherein The C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkoxy is optionally substituted with hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or heteroaryl.

In another embodiment of the invention, R ¹ is C _1-9 alkyl optionally substituted with hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or heteroaryl.

In yet another embodiment of the invention, R ¹ is C _1-6 alkyl optionally substituted with hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or heteroaryl.

According to one embodiment of the present invention, one carbon atom of the alkyl defined by R ¹ is substituted with at least one fluorine. According to another embodiment of the present invention, at least one carbon atom of the alkyl defined by R ¹ is substituted with O. According to yet another embodiment of the present invention, at least one carbon atom of the alkyl defined by R ¹ is substituted with NH, C (O), SO or SO ₂ . In yet another embodiment of the present invention, R ¹ is C _3-9 alkyl, and at least two carbon atoms of the alkyl defined by R ¹ are substituted with O. In yet another embodiment of the present invention, R ¹ is C _3-6 alkyl, and at least two carbon atoms of the alkyl defined by R ¹ are substituted with O. According to another embodiment of the present invention, at least one carbon atom of the alkyl defined by R ¹ is substituted with C (O).

In one embodiment of the invention, R ⁵ is C _3-6 cycloalkyl. According to another embodiment of the present invention, R ⁵ is C ₄ cycloalkyl or C ₆ cycloalkyl.
According to a further embodiment of the invention, R ⁵ is cyclobutyl or cyclohexyl or tetrahydropyran.

から選択され、そしてここで、Ｒ³は、場合により、ハロゲン、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ又はＣ_1-6ハロアルコキシで置換され；ここで、該Ｃ_1-6アルキル又はＣ_3-6シクロアルキルは、場合により、ハロゲン、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、アリール、ヘテロアリール、又はＣ、Ｎ及びＯから選択される４〜７個の原子から成る飽和の環系で置換され；ここで、該Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、アリール、ヘテロアリール又は環系は、場合により、Ｃ_1-4アルキルで置換され、そして、ここで、該Ｃ_1-4アルキルは、場合により、ＮＲ⁶Ｒ⁷、アリール、ヒドロキシ又はＣ_1-4アルコキシで置換される。 In another embodiment of the invention, R ³ is the following group:

And wherein R ³ is optionally substituted with halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, or C _1-6 haloalkoxy; C _1-6 alkyl or C _3-6 cycloalkyl is optionally halogen, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, aryl, heteroaryl, or C Substituted with a saturated ring system of 4 to 7 atoms selected from N, O and wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl or ring system is optionally substituted with C _1-4 alkyl, and wherein said C _1-4 alkyl is optionally NR ⁶ R ^7, aryl, optionally substituted with hydroxy or C _1-4 alkoxy.

であり、ここで、Ｒ³は、場合により、ハロゲン、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ又はＣ_1-6ハロアルコキシで置換され；ここで、該Ｃ_1-6アルキル又はＣ_3-6シクロアルキルは、場合により、ハロゲン、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、アリール、ヘテロアリール、又はＣ、Ｎ及びＯから選択される４〜７個の原子から成る飽和の環系で置換され；ここで、該Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、アリール、ヘテロアリール又は環系は、場合により、Ｃ_1-4アルキルで置換され；ここで、該Ｃ_1-4アルキルは、場合により、ＮＲ⁶Ｒ⁷、アリール、ヒドロキシ又はＣ_1-4アルコキシで置換される。 According to a further embodiment of the invention, R ³ has the following groups:

, And the wherein, R ³ is optionally halogen, C _1-6 alkyl, C _3-6 cycloalkyl, substituted with C _1-6 alkoxy or C _1-6 haloalkoxy; wherein said C _{1 -6} alkyl or C _3-6 cycloalkyl is optionally halogen, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, aryl, heteroaryl, or C, N Substituted with a saturated ring system of 4 to 7 atoms selected from and O; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl or ring system is optionally Substituted with C _1-4 alkyl; wherein the C _1-4 alkyl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy.

から選択され、ここで、Ｒ³は、場合により、ハロゲン、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ又はＣ_1-6ハロアルコキシで置換され、 ここで、該Ｃ_1-6アルキル又はＣ_3-6シクロアルキルは、場合により、ハロゲン、 ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシアリール 又はヘテロアリールで置換され；そして、ここで、該Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、アリール又はヘテロアリールは、場合により、Ｃ_1-4アルキルで置換され；ここで、該Ｃ_1-4アルキルは、場合により、ＮＲ⁶Ｒ⁷、アリール、ヒドロキシ又はＣ_1-4アルコキシで置換される。 Still according to a further embodiment of the present invention, R ³ represents the following group:

Wherein R ³ is optionally substituted with halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy, wherein the C 3 _1-6 alkyl or C _3-6 cycloalkyl is optionally substituted with halogen, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxyaryl or heteroaryl; and Wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally substituted with C _1-4 alkyl; wherein the C _1-4 alkyl is optionally Substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy.

According to another embodiment of the present invention, R ³ is naphthyl optionally substituted with halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy. Wherein the C _1-6 alkyl or C _3-6 cycloalkyl is optionally halogen, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, Substituted with a saturated ring system consisting of 4 to 7 atoms selected from aryl, heteroaryl or C, N and O; and wherein said C _1-6 alkyl, C _3-6 cycloalkyl, aryl, A heteroaryl or ring system is optionally substituted with C _1-4 alkyl; wherein the C _1-4 alkyl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy. The

According to yet another embodiment of the invention, R ³ is naphthyl substituted with C _1-6 alkyl; wherein the C _1-6 alkyl is substituted with heteroaryl; and The heteroaryl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy. In yet another embodiment, the C _1-6 alkyl is methyl. In a further embodiment of the invention the heteroaryl is 1,2,3-triazolyl.

から選択され、そしてここで、Ｒ³は、場合により、ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール又はヘテロアリールで置換される。 According to yet another embodiment of the invention, R ³ is the following group:

And wherein R ³ is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 halo Substituted with alkoxy, aryl or heteroaryl.

In another embodiment of the invention, R ³ is naphthyl substituted with methyl; wherein the methyl is substituted with 1,2,3-triazolyl; and wherein 1,2,3-triazolyl is C Substituted with _1-4 alkyl; wherein the C _1-4 alkyl is substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy.

から選択され；ここで、Ｒ³はＣ_1-6アルキルで置換され；ここで、該Ｃ_1-6アルキルは、場合により、ヘテロアリール、又はＣ、Ｎ及びＯから選択される４〜７個の原子より成る飽和の環系で置換され；ここで、該ヘテロアリール又は環系は、場合により、Ｃ_1-4アルキルで置換され；ここで、該Ｃ_1-4アルキルは、場合により、ＮＲ⁶Ｒ⁷、アリール、ヒドロキシ又はＣ_1-4アルコキシで置換され；
Ｒ⁴は、水素であり；
Ｒ⁵は、Ｃ_3-6シクロアルキルであり；
ｎは、１であり；
Ｒ⁶、Ｒ^6a、Ｒ⁷及びＲ^7aは、互いに独立に、水素及びＣ_1-6アルキルから選択され；
又は、Ｒ^6a及びＲ^7aは一緒になり、Ｃ、Ｏ及びＮから選択される４〜７個の原子から成る飽和の環系を形成し；その環系は場合により、Ｃ_1-6アルキル、 Ｃ_1-6アルコキシ、ハロゲン又はヒドロキシで置換され；
Ｒ¹で定義されるアルキル又はシクロアルキルの１つ又はそれ以上の炭素原子は、Ｏ、ＮＨ、Ｃ（Ｏ）、ＳＯ又はＳＯ₂で置換されても良く、そしてここで、Ｏ又はＮのいずれも別のＯ又はＮのいずれにも隣接せず、そして、ＳＯ又はＳＯ₂のいずれも別のＳＯ又はＳＯ₂のいずれにも隣接せず；
Ｒ²、Ｒ³及びＲ⁵で定義されたアルキル又はシクロアルキルの１つ又はそれ以上の炭素原子は、Ｏ、ＮＨ、Ｃ（Ｏ）又はＳＯ₂で置換されても良く、Ｏ又はＮのいずれも、別のＯ又はＮのいずれにも隣接せず；
Ｒ¹及びＲ³で定義されるアルキル又はシクロアルキルの１つ又はそれ以上の炭素原子は、フッ素で置換されても良く； そして
Ｒ³がＣ_1-4アルキル：ここで、Ｃ_1-4アルキルは、ヘテロアリール、Ｃ_3-6シクロアルキル、アリール、又はＣ、Ｏ及びＮから選択される４〜７個の原子から成る飽和の環系で置換され、ここで、該ヘテロアリール、Ｃ_3-6シクロアルキル又はアリールは、更に、Ｃ_1-4アルキル又はハロゲンで置換され、ここで、該Ｃ_1-4アルキルは、場合により、ＮＲ⁶Ｒ⁷、アリール、ヒドロキシ又はＣ_1-4アルコキシで置換され、そしてここで、該環系は、場合により、Ｃ_1-4アルキルで置換され、ここで、該Ｃ_1-4アルキルは、場合により、ＮＲ⁶Ｒ⁷、アリール、ヒドロキシ又はＣ_1-4アルコキシで置換される、で置換されない場合；又は、
Ｒ³が、下記の基：

ここで、Ｒ³は、場合により、ハロゲン、シアノ、ニトロ、ＮＲ⁶Ｒ⁷、Ｃ_1-6アルキル、Ｃ_3-6シクロアルキル、Ｃ_1-6アルコキシ、Ｃ_1-6ハロアルコキシ、アリール又はヘテロアリールで置換される；
から選択されない場合は、Ｒ²が、水素、ハロゲン、シアノ、アセチルアミノ、ヒドロキシ、Ｃ_1-6アルコキシ、Ｃ_1-6アルキル、Ｃ_1-6ハロアルコキシ、Ｃ_2-6アルケニル、Ｃ_1-6ハロアルキル、Ｃ_2-6ハロアルケニル及びＮＲ⁶Ｒ⁷の場合、同時にＲ¹が、水素、ハロゲン、シアノ、アセチルアミノ、ヒドロキシ、Ｃ_1-6アルコキシ、Ｃ_1-6アルキル、Ｃ_1-6ハロアルコキシ、Ｃ_2-6アルケニル、Ｃ_1-6ハロアルキル、Ｃ_2-6ハロアルケニル及びＮＲ⁶Ｒ⁷であることはない；
の化合物、又は薬学的に許容されるその塩、ジアステレオマー、エナンチオマー、若しくはその混合物である。 In one embodiment of the invention, R ¹ is hydrogen or C _1-9 alkyl; wherein said C _1-9 alkyl is optionally hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl Substituted with aryl or heteroaryl;
R ² is hydrogen or C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted with hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or heteroaryl;
R ³ represents the following group:

Wherein R ³ is substituted with C _1-6 alkyl; wherein the C _1-6 alkyl is optionally heteroaryl or 4-7 selected from C, N and O Wherein the heteroaryl or ring system is optionally substituted with C _1-4 alkyl; wherein the C _1-4 alkyl is optionally NR ⁶ R ⁷ , substituted with aryl, hydroxy or C _1-4 alkoxy;
R ⁴ is hydrogen;
R ⁵ is C _3-6 cycloalkyl;
n is 1;
R ⁶ , R ^6a , R ⁷ and R ^7a are independently of one another selected from hydrogen and C _1-6 alkyl;
Or R ^6a and R ^7a together form a saturated ring system of 4 to 7 atoms selected from C, O and N; the ring system is optionally C _1-6 alkyl, Substituted with C _1-6 alkoxy, halogen or hydroxy;
One or more carbon atoms of alkyl or cycloalkyl as defined for R ¹ may be substituted with O, NH, C (O), SO or SO ₂ , where either O or N Is not adjacent to any other O or N, and neither SO or SO ₂ is adjacent to any other SO or SO ₂ ;
One or more carbon atoms of alkyl or cycloalkyl as defined for R ² , R ³ and R ⁵ may be substituted with O, NH, C (O) or SO ₂ and either O or N Is not adjacent to any other O or N;
One or more carbon atoms of the alkyl or cycloalkyl defined by R ¹ and R ³ may be substituted with fluorine; and R ³ is C _1-4 alkyl: where C _1-4 alkyl Is substituted with a heteroaryl, C _3-6 cycloalkyl, aryl, or a saturated ring system of 4-7 atoms selected from C, O and N, wherein the heteroaryl, C _{3- 6} cycloalkyl or aryl is further substituted with C _1-4 alkyl or halogen, wherein the C _1-4 alkyl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy. in is, and wherein the said ring system is optionally substituted by C _1-4 alkyl, wherein said C _1-4 alkyl is optionally NR ⁶ R ^7, aryl, hydroxy or C _1-4 Substituted with alkoxy, not substituted with Or,
R ³ is the following group:

Wherein R ³ is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or hetero Substituted with aryl;
R ² is hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _1-6 In the case of haloalkyl, C _2-6 haloalkenyl and NR ⁶ R ⁷ , at the same time R ¹ is hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy , C _2-6 alkenyl, C _1-6 haloalkyl, C _2-6 haloalkenyl and NR ⁶ R ⁷ ;
Or a pharmaceutically acceptable salt, diastereomer, enantiomer, or mixture thereof.

According to a further embodiment of the invention, A ¹ is N and A ² is N.
According to yet another embodiment of the present invention, A ¹ is N and A ² is CH.

In another embodiment of the invention, R ¹ is selected from hydrogen or C _1-6 alkyl; said C _1-6 alkyl is optionally hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or Substituted with heteroaryl;
R ² is hydrogen;
R ³ is optionally substituted with halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or heteroaryl Wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C Substituted with _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl, or heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl, or heteroaryl is Optionally further substituted with C _1-4 alkyl; wherein the C _1-4 alkyl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy;
R ⁴ is hydrogen;
R ⁵ is C _3-6 cycloalkyl;
R ⁶ is hydrogen or C _1-4 alkyl;
R ⁷ is hydrogen or C _1-4 alkyl;
R ^6a is hydrogen or C _1-4 alkyl; and R ^7a is hydrogen or C _1-4 alkyl.

The invention also relates to compounds selected from the following compounds:
[(6-{[(cyclohexylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy ] Methyl acetate;
[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) Oxy] methyl acetate;
[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) Oxy] acetic acid;
6- (2-Amino-2-oxoethoxy) -N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-carboxamide;
N- (cyclobutylmethyl) -6- [2- (methylamino) -2-oxoethoxy] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] Amino} pyridine-2-carboxamide;
N- (cyclobutylmethyl) -6- [2- (dimethylamino) -2-oxoethoxy] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] Amino} pyridine-2-carboxamide;
N- (cyclobutylmethyl) -6- {2-[(2-hydroxyethyl) amino] -2-oxoethoxy} -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide;
Ethanesulfonic acid 6-{[(cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl ;
3,3,3-trifluoropropane-1-sulfonic acid 6-{[(cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl)- 1-naphthoyl] amino} pyridin-2-yl;
3,3,3-trifluoropropane-1-sulfonic acid 6-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole -1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl;
Acetic acid 6-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-yl;
N- (cyclobutylmethyl) -6- (2-hydroxyethoxy) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide ;
N- (cyclobutylmethyl) -6- [2- (2-hydroxyethoxy) ethoxy] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} Pyridine-2-carboxamide;
6- (Benzyloxy) -N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-carboxamide;
3-Benzyl-1-[(4-{[(6- (benzyloxy) -2-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} pyridin-3-yl) amino] carbonyl}- 1-naphthyl) methyl] -1H-1,2,3-triazole-3-ium;
N- (cyclobutylmethyl) -6- (pyridin-2-ylmethoxy) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2- Carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[5- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[5- (1-hydroxyethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine- 2-carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[4- (1-hydroxyethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine- 2-carboxamide;
3-[(4-{[5- (aminocarbonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] -N- (cyclobutylmethyl) pyridine-2- Carboxamide;
3-[(4-{[4- (Aminocarbonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] -N- (cyclobutylmethyl) pyridine-2- Carboxamide;
6- (aminomethyl) -N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide;
N- (cyclobutylmethyl) -6- (hydroxymethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide;
N- (cyclobutylmethyl) -6-{[(methylsulfonyl) amino] methyl} -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-carboxamide;
6-{[(cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} methyl pyridine-2-carboxylate;
N ^2- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2,6-dicarboxamide; and N- ( Cyclobutylmethyl) -6-methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1- Naphthoyl] amino} pyrazine-2-carboxamide.

The invention also relates to compounds selected from the following compounds:
6- (2-morpholin-4-yl-2-oxoethoxy) -3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2- Carboxylic acid cyclobutylmethyl-amide;
6- (benzylcarbamoyl-methoxy) -3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid cyclobutylmethyl-amide;
{6- (Cyclobutylmethyl-carbamoyl) -5-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridin-2-yloxy} -acetic acid 2, 2-dimethylpropyl ester;
{6- (Cyclobutylmethyl-carbamoyl) -5-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridin-2-yloxy} -acetic acid isopropyl ester ;
6-hydroxycarbamoylmethoxy-3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid cyclobutylmethyl-amide;
6- (methoxycarbamoyl-methoxy) -3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid cyclobutylmethyl-amide;
{5-[(4-Methyl-naphthalene-1-carbonyl) -amino] -6-[(tetrahydro-pyran-4-ylmethyl) -carbamoyl] -pyridin-2-yloxy} -acetic acid methyl ester;
6-carbamoylmethoxy-3-[(4-methyl-naphthalen-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
{5-[(4-Methyl-naphthalene-1-carbonyl) -amino] -6-[(tetrahydro-pyran-4-ylmethyl) -carbamoyl] -pyridin-2-yloxy} -acetic acid;
6- (2-hydroxy-ethoxy) -3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6- (2-hydroxy-ethoxy) -3-[(4-methoxymethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-methanesulfonyl-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-methanesulfinyl-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6- [2- (2-hydroxy-ethoxy) -ethoxy] -3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid Acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-methoxy-3-({4-[(4-methylpiperazin-1-yl) methyl] -1-naphthoyl} amino) -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
6-methoxy-3-{[4- (morpholin-4-ylmethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
6-[(ethylamino) sulfonyl] -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
6- (benzylsulfonyl) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
6- (benzylsulfonyl) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
3,3,3-trifluoropropane-1-sulfonic acid 6-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] -5-{[4- (1H-1,2,3-triazole-1- Ylmethyl) -1-naphthoyl] amino} pyrazin-2-yl;
N- (cyclobutylmethyl) -3-{[4-({5-[(dimethylamino) methyl] -1H-1,2,3-triazol-1-yl} methyl) -1-naphthoyl] amino} pyridine -2-carboxamide;
N- (cyclobutylmethyl) -3-{[4-({4-[(dimethylamino) methyl] -1H-1,2,3-triazol-1-yl} methyl) -1-naphthoyl] amino} pyridine -2-carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[4- (trifluoromethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2 A carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[5- (phenylsulfonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[4- (phenylsulfonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide;
N- (cyclobutylmethyl) -3-({4-[(4-fluoro-1H-1,2,3-triazol-1-yl) methyl] -1-naphthoyl} amino) pyridine-2-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1-methyl-1H-indole-3-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1-methyl-1H-indole-2-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1H-indole-3-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] -4-methoxyphenyl} quinoline-4-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] -6-methoxypyridin-3-yl} -1-methyl-1H-indazole-3-carboxamide;
3-[(1-benzothien-3-yl-carbonyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
3-[(5,6,7,8-tetrahydronaphthalen-1-ylcarbonyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
N- {2-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1H-indazole-3-carboxamide;
N- {2-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1H-indole-3-carboxamide;
1-methyl-N- {2-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1H-indole-3-carboxamide;
N- {2-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1,3-benzothiazole-6-carboxamide;
N- {2-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1,6-naphthyridine-5-carboxamide;
3-{[(6-fluoro-4H-1,3-benzodioxin-8-yl) carbonyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1H-indazole-3-carboxamide; and 3-[(4-{[(5-methylisoxazol-3-yl) methoxy] Methyl} -1-naphthoyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide.

The invention also relates to a compound selected from:
N- (cyclobutylmethyl) -6-hydroxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide;
6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2- Carboxamide;
3-[(4-{[5- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] methyl pyridine-2-carboxylate;
3-[(4-{[4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] methyl pyridine-2-carboxylate;
3-{[4- (azidomethyl) -1-naphthoyl] amino} methyl pyridine-2-carboxylate;
6-cyano-N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide;
Methyl 6-cyano-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate;
Methyl 6-chloro-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate;
6-methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine -2-carboxylic acid;
6-methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine Methyl-2-carboxylate;
Methyl 5-chloro-6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2-carboxylate;
Methyl 5-chloro-6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyrazine-2-carboxylate;
Methyl 6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyrazine-2-carboxylate;
Methyl 3-amino-6-methoxypyrazine-2-carboxylate;
3-amino-6-methoxypyrazine-2-carboxylic acid;
6-bromo-3- (3-chlorophenyl) pteridine-2,4 (1H, 3H) -dione;
3-{[4- (bromomethyl) -1-naphthoyl] amino} methyl pyridine-2-carboxylate;
Methyl 3-amino-6-bromopyrazine-2-carboxylate;
6-hydroxy-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-hydroxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2- Carboxamide;
3-[(4-methyl-naphthalene-1-carbonyl) -amino] -6-methylsulfanyl-pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-chloro-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-chloro-3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
3-{[4- (bromomethyl) -1-naphthoyl] amino} -6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
6- (benzylthio) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
Methyl 5-methoxy-2-[(quinolin-4-ylcarbonyl) amino] benzoate; and 6-methoxy-3-{[(1-methyl-1H-indazol-3-yl) carbonyl] amino} pyridine-2 -Methyl carboxylate.

The present invention also relates to the use of the above compounds in a process for preparing the compounds according to the invention.

  The invention also relates to a pharmaceutical composition comprising as active ingredient a compound of formula (I) as defined above and a pharmaceutically acceptable carrier or excipient.

The compounds of the present invention have activity as drugs, in particular as modulators or ligands such as agonists, semi-agonists, inverse agonists or antagonists of the CB ₁ receptor. More specifically, the compounds of the present invention exhibit activity as agonists of the CB ₁ receptor and are particularly useful for treatment, particularly various gastrointestinal disorders such as gastroesophageal reflux disease, constipation, irritable bowel syndrome (IBS) and Useful for alleviating functional gastrointestinal disorders such as functional dyspepsia (FD). The compounds of the present invention are also useful for alleviating various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, back pain, rheumatoid arthritis pain, migraine, visceral pain. However, these lists should not be interpreted as exhaustive. In addition, the compounds of the present invention are useful in other disease states where CB ₁ receptor dysfunction exists or is associated. Furthermore, the compounds of the invention can be used for the treatment of cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, anxiety disorders, and cardiovascular disorders.

  The compounds of the invention are used especially for autoimmune diseases such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases and various allergies, and as anticancer and antiviral agents Therefore, it is useful as an immunomodulator.

  The compounds of the present invention are useful in disease states where the cannabinoid receptor degeneration or dysfunction is present or associated in the case. This can include the use of isotopically labeled compounds of the present invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).

  The compounds of the present invention may also contain diarrhea; depression; post-traumatic stress disorder, panic disorder, generalized anxiety disorder, anxiety and stress related diseases such as social phobia and obsessive compulsive disorder; urinary incontinence; premature ejaculation; Diseases; cough; pulmonary edema; Parkinson's disease and other movement disorders; traumatic brain injury; cerebral infarction; cardioprotection after myocardial infarction; spinal cord injury; and drug addiction including treatment of alcohol, nicotine, opioids and other drug abuse As well as for sympathetic nervous system diseases such as hypertension.

  The compounds of the present invention are useful as analgesics for use during general anesthesia and monitoring anesthesia. Combinations of drugs with different properties are often used to balance the effects necessary to sustain anesthesia (eg, memory loss, analgesia, muscle relaxation and sedation). Included in this combination are inhalation anesthetics, sleep aids, anxiolytics, neuromuscular blockers and opioids.

  Another aspect of the present invention is the use of a compound according to formula (I) for the inhibition of transient lower esophageal sphincter relaxation (TLESR) and thus the treatment or prevention of gastroesophageal reflux disease (GERD). The main mechanism involved in reflux is thought to depend on the hypotonic lower esophageal sphincter. However, for example, Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535 states that most reflux episodes occur during transient lower esophageal sphincter relaxation (TLESR), ie relaxation. Indicates that it is not induced by swallowing. In yet a further embodiment of the invention, the compound of formula (I) is used to prevent reflux, treat or prevent reflux, treat or prevent asthma, treat or prevent laryngitis, treat or prevent lung disease. , And useful for the management of growth disorders.

  A further aspect of the invention is the treatment or prevention of asthma to prevent transient lower esophageal sphincter relaxation (TLESR), to treat or prevent GERD, to prevent reflux, to treat or prevent reflux. Use of a compound according to formula (I) for the manufacture of a medicament for the treatment or prevention of laryngitis, the treatment or prevention of pulmonary diseases and the management of growth disorders.

  Yet another aspect of the invention is the use of a compound according to formula (I) for the manufacture of a medicament for treating or preventing a functional gastrointestinal disorder such as functional dyspepsia (FD). Yet another aspect of the present invention is the use of a compound according to formula (I) for the manufacture of a medicament for treating or preventing irritable bowel syndrome (IBS) such as constipation type IBS, diarrhea type IBS, alternation type IBS, etc. It is. Functional gastrointestinal diseases (FGD) such as typical irritable bowel syndrome (IBS) and functional dyspepsia (FD) are Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Mueller-Lissner SA. C. Functional Bowel Disorders and Functional Abdominal Pain.In: Drossman DA, Talley NJ, Thompson WG, Whitehead WE, Coraziarri E, eds. Rome II: Functional Gastrointestinal Disorders: Diagnosis, Pathophysiology and Treatment. 2 ed. McLean, VA: Degnon Associates, Inc .; 2000: 351-432 and Drossman DA, Corazziari E, Talley NJ, Thompson WG and Whitehead WE. Rome II: A multinational consensus document on Functional Gastrointestinal Disorders.Gut 45 (Suppl. 2), II1-II81 It is explained in detail in .9-1-1999.

  The use of any of the compounds described in Formula (I) above for the manufacture of a medicament for treating any of the conditions discussed above is within the scope of the invention.

  A further aspect of the invention is a method of treating a subject suffering from any of the conditions discussed above, wherein an effective amount of a compound described in formula (I) above is administered to the patient in need of such treatment. Is a treatment administered to the patient.

  Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as previously defined for use in therapy.

  In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as previously defined in the manufacture of a medicament for use in therapy.

  As used herein, the term “treatment” includes “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be construed accordingly. In the context of the present invention, the term “treatment” further administers an effective amount of a compound of the present invention to alleviate a pre-existing condition, either acute or chronic, or recurrent. To include. This definition also includes prophylactic treatment to prevent recurrent conditions and continuous treatment for chronic diseases. The compounds of the present invention are useful for the treatment of various pain conditions including, but not limited to, acute pain, chronic pain, neuropathic pain, back pain, cancer pain and visceral pain.

  For use in therapy in warm-blooded animals such as humans, the compounds of the invention are in the form of conventional pharmaceutical compositions, oral, intramuscular, subcutaneous, topical, intranasal, intraperitoneal, intrathoracic, intravenous, It may be administered by epidural, any route including intrathecal, and intra-articular injection.

  A further aspect of the invention is a method of treating a subject suffering from any of the conditions discussed above, wherein an effective amount of the compound described in Formula (I) above is in need of such treatment. Is a treatment administered to the patient.

Formulation Formulation In one embodiment of the invention, the route of administration may be buccal, intravenous or intramuscular.

  The dosage will depend on the route of administration, the severity of the illness, the age and weight of the patient, and other factors normally considered by the attending physician in determining the individual dosage regimen and the most appropriate dosage level for a particular patient.

  For preparing pharmaceutical compositions from the compounds of the present invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.

  A solid carrier can also be one or more substances that function as excipients, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents, and are encapsulating materials. May be.

  In powders, the carrier is a finely divided solid, which exists as a mixture with the finely divided compound of the invention, ie, the active component. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compressed to the desired shape and size.

  For preparing suppository compositions, a low-melting fat such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient molds and allowed to cool and harden.

  Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.

  The term {composition} is also intended to include a formulation of an active ingredient and an encapsulant as a carrier to provide a capsule, in which the active ingredient is (along with other carriers or By itself, it is thus surrounded by a carrier that is associated with the active ingredient.

  Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

  Liquid compositions include solutions, suspensions and emulsions. For example, sterile water or water-propylene glycol solutions of the active ingredient are liquid formulations suitable for parenteral administration. Liquid compositions can also be formulated as aqueous polyethylene glycol solutions.

  Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as necessary. Orally used aqueous suspensions can be used to dissolve the finely divided active ingredient in water, along with viscous substances such as natural, synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose and other suspensions known in the pharmaceutical formulation industry. It can be prepared by dispersing.

  Depending on the method of administration, the pharmaceutical composition may comprise from 0.05% to 99% by weight of the invention according to one embodiment and from 0.10% to 50% by weight of the invention according to another embodiment. Contains all compounds and all weight percentages are based on total composition.

  The therapeutically effective amount for practicing the present invention is determined by one of skill in the art using known criteria, including the age, weight and response of the individual patient, and interpreted within the scope of the disease to be treated or prevented be able to. A typical daily dose of a cannabinoid receptor agonist is 0.1 to 10 mg, which depends on various factors such as method of administration, patient age and weight, and severity of the patient's condition.

  There is also provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

  The invention also relates to a therapeutic pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient.

  Further provided is a pharmaceutical composition for use in any of the above-discussed conditions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ａ¹、Ａ²及びｎは、上記で定義された通りである）の化合物を製造する方法であって、
（ｉ）式（II）の化合物：

を、ＣＨ₂Ｃｌ₂の様な溶媒中で、ＤＩＰＥＡの様な塩基の存在下、Ｒ³ＣＯＣｌと反応させ、それにより、式（III）を得ること（ここで、Ｒ¹、Ｒ²、Ｒ³、Ａ¹及びＡ²は上記で定義した通りである）；
（ii）工程（ｉ）から得られた式（III）の化合物：

を、ＤＭＦの様な溶媒中、Ｒ⁴（ＣＨ₂）_nＲ⁵ＮＨと反応させること（ここで、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、ｎ、Ａ¹及びＡ²は、上記で定義した通りである）；
を含む製造方法を提供する。 Production Method The present invention provides a compound of formula (I):

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A ¹ , A ² and n are as defined above, comprising the steps of:
(I) Compound of formula (II):

Is reacted with R ³ COCl in the presence of a base such as DIPEA in a solvent such as CH ₂ Cl ₂ , thereby obtaining formula (III) (where R ¹ , R ² , R ³ , A ¹ and A ² are as defined above);
(Ii) Compound of formula (III) obtained from step (i):

Is reacted with R ⁴ (CH ₂ ) _n R ⁵ NH in a solvent such as DMF (where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n, A ¹ and A ² are , As defined above);
A manufacturing method is provided.

The compounds of the present invention can also be prepared according to synthetic routes as depicted in Schemes 1-4. In schemes 1 to 4, R ¹ , R ² , A ¹ , A ² , R ³ , R ⁴ , R ⁵ , n, R ⁶ and R ⁷ are as defined above unless otherwise specified.

Scheme 1: Synthetic route used for the synthesis of the examples

Scheme 2: Synthesis route used for the synthesis of example, where, R ⁹ is optionally, NR ⁶ R ^7, aryl, C _1-4 alkyl substituted with hydroxy or C _1-4 alkoxy

Scheme 3: Synthetic route used for the synthesis of the examples

Scheme 4: Synthetic route used for the synthesis of the examples, where A ¹ and A ² are N

一般式（IV）の化合物をＭｅＯＨ（１０ｍＬ／ｍｍｏｌ）に溶解し、そして、ＴＭＳＣｌ（１０当量）又はＨＣｌ（気体）で４８時間室温で処理した。溶媒を減圧下で除去し、そして残留物をＣＨ₂Ｃｌ₂に溶解し、飽和のＮａＨＣＯ₃水溶液で洗浄し、一般式（Ｖ）の化合物を得た。 General procedure
General procedure 1 (where R ¹ and R ² are as defined above):

The compound of general formula (IV) was dissolved in MeOH (10 mL / mmol) and treated with TMSCl (10 eq) or HCl (gas) for 48 h at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ to give a compound of general formula (V).

一般式（VI）の化合物を、対応するカルボン酸からオキサリルクロリド（１.３→３当量）を用い、ＣＨ₂Ｃｌ₂（８ｍＬ／ｍｍｏｌ）中、室温で、２→１６時間処理することにより調製した。溶媒を減圧下で除去し、一般式（II）の化合物を得た。 General procedure 2 (where R ³ is as defined above):

Prepared by treatment of compound of general formula (VI) from the corresponding carboxylic acid with oxalyl chloride (1.3 → 3 eq) in CH ₂ Cl ₂ (8 mL / mmol) at room temperature for 2 → 16 hours. did. The solvent was removed under reduced pressure to obtain a compound of general formula (II).

一般式（VII）の化合物を、ＣＨＣｌ₃（２.５ｍＬ／ｍｍｏｌ）に溶解し、そしてピリジン（５→１０当量）及び４−ジメチルアミノピリジン（ＤＭＡＰ、０.３当量）で処理した。反応混合物を５０→６０℃に加熱し、そして一般式（VI）の化合物（１.５当量）と、ＣＨＣｌ₃（１.７ｍＬ／ｍｍｏｌ及びピリジン０→１０当量）中で処理した。反応を５０→６０℃で、１→２時間進行させ、一般式（VIII）の化合物を得た。 General procedure 3 (where R ¹ , R ² and R ³ are as defined above):

The compound of general formula (VII) was dissolved in CHCl ₃ (2.5 mL / mmol) and treated with pyridine (5 → 10 eq) and 4-dimethylaminopyridine (DMAP, 0.3 eq). The reaction mixture was heated to 50 → 60 ° C. and treated with a compound of general formula (VI) (1.5 eq) in CHCl ₃ (1.7 mL / mmol and pyridine 0 → 10 eq). The reaction was allowed to proceed at 50 → 60 ° C. for 1 → 2 hours to obtain a compound of general formula (VIII).

一般式（VIII）の化合物をＤＭＦ（１０ｍＬ／ｍｍｏｌ）に溶解し、そして一般式Ｈ₂ＮＣＨ₂Ｒ⁴（３→６当量）のアミンと、８０→１００℃で、３→６時間処理して、一般式（IX）の化合物を得た。 General procedure 4 (where R ¹ , R ² , R ³ and R ⁴ are as defined above):

The compound of general formula (VIII) is dissolved in DMF (10 mL / mmol) and treated with an amine of general formula H ₂ NCH ₂ R ⁴ (3 → 6 eq) at 80 → 100 ° C. for 3 → 6 hours. To obtain a compound of the general formula (IX).

一般式（IV）の化合物をＣＨ₂Ｃｌ₂（４ｍＬ／ｍｍｏｌ）に溶解し、そしてＤＩＰＥＡ（３→５当量）、一般式Ｈ₂ＮＣＨ₂Ｒ⁴のアミン（１.２当量）及びＴＢＴＵ（１.３当量）で、室温において１→２時間処理して、一般式（Ｘ）の化合物を得た。 General procedure 5 (where R ⁴ is as defined above and R ¹ and R ² are hydrogen):

The compound of general formula (IV) is dissolved in CH ₂ Cl ₂ (4 mL / mmol) and DIPEA (3 → 5 eq), amine of general formula H ₂ NCH ₂ R ⁴ (1.2 eq) and TBTU (1 .3 equivalents) at room temperature for 1 to 2 hours to give compounds of general formula (X).

一般的手順６ｂ（ここで、Ｒ¹、Ｒ²、Ｒ³及びＲ⁴は、上記で定義した通りである）：
一般式（Ｘ）の化合物をＤＭＦ（６ｍＬ／ｍｍｏｌ）に溶解し、そしてＤＩＰＥＡ（２当量）、一般式（IV）の酸（１当量）及びＴＢＴＵ（１当量）と、室温で１→２時間処理して、一般式（IX）の化合物を得た。 General procedure 6 (where R ¹ , R ² , R ³ and R ⁴ are as defined above):
The compound of general formula (X) dissolved in CH ₂ Cl ₂ (5 mL / mmol) and DIPEA (10 eq) and dissolved in CH ₂ Cl ₂ (5 mL / mmol) (3 eq) ) At room temperature. The reaction was allowed to proceed at room temperature overnight (16 hours) to obtain a compound of the general formula (V).

General procedure 6b (where R ¹ , R ² , R ³ and R ⁴ are as defined above):
The compound of general formula (X) is dissolved in DMF (6 mL / mmol) and with DIPEA (2 eq), acid of general formula (IV) (1 eq) and TBTU (1 eq) at room temperature for 1 → 2 hours. Treatment gave a compound of general formula (IX).

Biological evaluation
The hCB ₁ and hCB ₂ receptor binding membranes were isolated from human CB ₂ receptor (hCB ₂ ) cloned using HEK293S cells expressing the cloned human CB ₁ receptor (hCB ₁ : clone # 24) or the baculovirus system. ) From any of the Sf9 cells expressing. The membrane was thawed at 37 ° C. and passed through a 23-gauge needle with a blunt tip three times. The cannabinoid binding buffer [Tris (50 mM), EDTA (2.5 mM), MgCl ₂ (5 mM) and fatty acid-free BSA (0 0.5 mg / mL), pH 7.4], and dispense an aliquot containing the appropriate amount of protein into a 96 well plate. The IC ₅₀ of hCB ₁ and hCB ₂ of the compound of the present invention is 10 points measured with ³ H-CP55,940 at a final solution volume of 300 μL and 20,000-25,000 dpm (0.17-0.21 nM) per well The dose response curve is evaluated. Total binding and non-specific binding are measured in the presence and absence of 0.2 μM HU210, respectively. Plates were vortexed and incubated for 60 minutes at room temperature, then using 3 mL wash buffer [Tris (50 mM), MgCl ₂ (5 mM), BSA (0.5 mg), pH 7.4]] and Unifilters GF using a Packard harvester. Filter with / B (previously soaked in polyethyleneimine (0.1%)). The filter is dried at 55 ° C. for 1 hour. Radioactivity (cpm) is measured in TopCount (Packard) after adding 65 μL / well of MS-20 scintillation fluid.

hCB ₁ ・ GTPγS binding
The cloned human CB ₁ receptor (hCB ₁ ) obtained from Perkin-Elmer was thawed at 37 ° C., passed through a 23-gauge needle with a blunt tip three times, and GTPγS binding buffer [Hepes (50 mM), NaOH ( 20 mM), NaCl (100 mM), EDTA (1 mM), MgCl ₂ (5 mM), pH 7.4, BSA (0.1%)]. The EC ₅₀ and E _max of the compounds of the invention were measured with 100,000 to 130,000 dpm (0.11 to 0.14 nM) GTPγ ³⁵ S per well in 300 μL containing the appropriate amount of membrane protein 10 Evaluate from point dose response curves. Basal binding and maximal stimulus binding are measured in the presence and absence of 10 μM Win55,212-2. Membranes are pre-incubated with 112.5 μM GDP for 5 minutes (final 30 μM GDP) prior to dispensing to plates. Plates were vortexed and incubated at room temperature for 60 minutes, then using 3 mL wash buffer [Tris (50 mM), MgCl ₂ (5 mM), NaCl (50 mM), pH 7.0]] and Unifilters GF / B using a Packard harvester. Filter by (soaked in water beforehand). The filter is dried at 55 ° C. for 1 hour. Radioactivity (cpm) is measured in TopCount (Packard) after adding 65 μL / well of MS-20 scintillation fluid.

Based on the above assay, the dissociation constant (Ki) for a particular receptor of a particular compound of the invention is determined using the following formula:
Ki = IC ₅₀ / (1+ [rad] / Kd)
Where IC ₅₀ is the concentration of the compound of the invention when 50% substitution is observed; [rad] is the standard or control radioligand concentration at that time; This is the dissociation constant of the radioactive ligand for the receptor.

By using the above assay, the Ki of most compounds of the invention for the human CB ₁ receptor is measured and is in the range of 2-5,000 nM. The E _max of most of the compounds of the invention for the human CB ₁ receptor is measured and is in the range of about 0-150%.

The table below shows certain biological activities of some of the exemplified compounds.

Screening for compounds active against TLESR Male and female Labrador Retrievers trained to withstand Pavlov sling were used. A mucosal-cutaneous esophageal fistula was performed and allowed to fully recover before any experiments were performed.

Motility measurement Briefly, a multi-lumen sleeve with side holes is used to measure gastric, lower esophageal sphincter (LES) and esophageal pressure after fasting for about 17 hours under a free supply of water. The assembly (Dentsleeve, Adelaide, South Australia) is introduced by esophageal fistula construction. The circuit is perfused with a low compliance pressure sensing perfusion pump (Dentsleeve, Adelaide, South Australia). To measure swallowing, a tube perfused with air is passed through the mouth and the pH is monitored 3 cm above the LES with an antimony electrode. All signals are amplified and captured on a personal computer at 10 Hz.

  When baseline measurements without fasting stomach / LES phase III motility activity were obtained, placebo (vehicle) or test compound was administered intravenously (iv, 0.5 mg / kg) or orally (i.e., 0.5 mg / kg). p.o., 2 mg / kg). 10 minutes after i.v. administration or 30 minutes after p.o. administration, a nutritional diet [peptone (10%), D-glucose (5%), intralipid (5%), pH 3.0] circuit A final volume of 30 mL / kg is injected into the stomach at 100 mL / min through the central lumen of the stomach. Immediately after the meal, blow air at 40 mL / min. In another model (Barostat model), air is blown at 500 mL / min until the gastric pressure is 10 ± 1 mmHg after injecting nutrients. Subsequently, the pressure is maintained at this level throughout the experiment, using an infusion pump to inject more air or to expel air from the stomach. The experiment time from the start of injecting nutritional food to the end of air blowing is 45 minutes. The method is certified as a reliable TLESR inducer.

  TLESR is defined as a decrease in lower esophageal sphincter pressure (relative to intragastric pressure) at a rate of> 1 mmHg / sec. The relaxation must not be preceded by a <2 second pharyngeal signal before relaxation begins; if so, the relaxation is classified as swallowing induced. The pressure difference between LES and stomach is less than 2 mm Hg and the time of complete relaxation must be longer than 1 second.

  Inhibition of the TLESR number was calculated from each dog's control experiment.

  The invention is explained in more detail in the following examples. They describe methods by which the compounds of the invention can be prepared, purified, analyzed, and subjected to biological tests, but should not be construed as limiting the invention.

  Unless otherwise noted, compounds were flash chromatographed using a pre-packed Biotage Si 25 + M column and a Horizon / Biotage system using heptane / ethyl acetate (1 / 0-1 / 2) as the eluent. Purified with.

Example 1
[(6-{[(cyclohexylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy ] Methyl acetate

実施例１Ｂで製造したＮ−（シクロヘキシルメチル）−６−ヒドロキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（２０ｍｇ、０.０４ｍｍｏｌ）、炭酸銀（５７ｍｇ、０.２１ｍｍｏｌ）及びブロモ酢酸メチル（１９ｍｇ、０.１２ｍｍｏｌ）のアセトニトリル（２.５ｍｌ）中の混合物を５０分間還流した。反応混合物を室温まで放置し、次いでジクロロメタンで希釈し、そして濾過した。濾液を水で洗浄し、乾燥し、減圧下で蒸発させた。残留物を、溶離液として、ＣＨ₂Ｃｌ₂／ＭｅＯＨを用いたシリカゲル上でのカラムクロマトグラフィーで精製し、標題の化合物（１４ｍｇ、６３％）を得た。
¹Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：０.９４−１０４ （ｍ，２Ｈ），１.１２−１.３１（ｍ，３Ｈ），１.５１−１.６１（ｍ，１Ｈ），１.６２−１.８０（ｍ，５Ｈ），３.２１（ｔ，Ｊ＝６.６Ｈｚ，２Ｈ），３.７５（ｓ，３Ｈ），４.８０（ｓ，２Ｈ），６.０６（ｓ，２Ｈ）， ７.１６（ｄ，Ｊ＝９.４Ｈｚ，１Ｈ），７.３９（ｄ，Ｊ＝１Ｈｚ，１Ｈ），７.４３（ｄ，Ｊ＝７.０Ｈｚ，１Ｈ），７.５５−７.６２（ｍ，２Ｈ），７.６９（ｄ，Ｊ＝１Ｈｚ，１Ｈ），７.８４（ｄ，Ｊ＝７.５Ｈｚ，１Ｈ），７.９５（ｔ，Ｊ＝６.１Ｈｚ，１Ｈ），８.０１（ｄｄ，Ｊ＝７.０， ２.３５Ｈｚ，１Ｈ），８.５４（ｄｄ，Ｊ＝７.０，２.４Ｈｚ，１Ｈ），９.４１（ｄ，Ｊ＝８.９Ｈｚ，１Ｈ），１２.６６（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺ ４８５.１５。 Example 1A
[(6-{[(cyclohexylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy ] Methyl acetate

N- (cyclohexylmethyl) -6-hydroxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide prepared in Example 1B A mixture of (20 mg, 0.04 mmol), silver carbonate (57 mg, 0.21 mmol) and methyl bromoacetate (19 mg, 0.12 mmol) in acetonitrile (2.5 ml) was refluxed for 50 minutes. The reaction mixture was allowed to reach room temperature then diluted with dichloromethane and filtered. The filtrate was washed with water, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ / MeOH as eluent to give the title compound (14 mg, 63%).
¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 0.94-104 (m, 2H), 1.12-1.31 (m, 3H), 1.51-1.61 (m, 1H) ), 1.62-1.80 (m, 5H), 3.21 (t, J = 6.6 Hz, 2H), 3.75 (s, 3H), 4.80 (s, 2H), 6. 06 (s, 2H), 7.16 (d, J = 9.4 Hz, 1H), 7.39 (d, J = 1 Hz, 1H), 7.43 (d, J = 7.0 Hz, 1H), 7.55-7.62 (m, 2H), 7.69 (d, J = 1 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.95 (t, J = 6) .1 Hz, 1 H), 8.01 (dd, J = 7.0, 2.35 Hz, 1 H), 8.54 (dd, J = 7.0, 2.4 Hz, 1 H), 9.41 (d, J = 8.9 Hz, 1H), 12.66 (s, 1H); MS (ESI) (M + H) ^<+ > 485.15.

実施例１Ｃで製造した、Ｎ−（シクロヘキシルメチル）−６−メトキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（０.２９ｇ、０.５８ｍｍｏｌ）及びピリジン塩酸塩（７.３ｇ、６３.１７ｍｍｏｌ）の混合物を、１５０℃で２５分間加熱した。室温で水を加えた。生成した沈殿物を集め、水で洗浄し、乾燥し、次いで、アセトニトリル及び酢酸アンモニウム緩衝液（２５／７５〜９５／５）を用いて分取型ＨＰＬＣで精製し、標題の化合物（１９３ｍｇ、６９％）を得た。
¹Ｈ−ＮＭＲ（５００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：０.９２−１.０２（ｍ，２Ｈ），１.１２−１.３０（ｍ，３Ｈ），１.５０−１.６０（ｍ，１Ｈ），１.６２−１.７８（ｍ，５Ｈ），３.１５（ｄ，Ｊ＝７.０Ｈｚ，２Ｈ），６.１９（ｓ，２Ｈ），６.９６（ｄ，Ｊ＝８.９Ｈｚ，１Ｈ），７.４７（ｄ，Ｊ＝７.０Ｈｚ，１Ｈ），７.６０−７.６６（ｍ，２Ｈ），７.７３（ｄ，Ｊ＝０.９Ｈｚ，１Ｈ），７.８４（ｄ，Ｊ＝７.０Ｈｚ，１Ｈ），７.９４（ｄ，Ｊ＝０.９Ｈｚ，１Ｈ），８.１９−８.２４（ｍ，１Ｈ），８.４３−８.４８（ｍ，１Ｈ），９.１２（ｄ，Ｊ＝８.９Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４８５.１５。 Example 1B
N- (cyclohexylmethyl) -6-hydroxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide

N- (cyclohexylmethyl) -6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-prepared in Example 1C A mixture of carboxamide (0.29 g, 0.58 mmol) and pyridine hydrochloride (7.3 g, 63.17 mmol) was heated at 150 ° C. for 25 minutes. Water was added at room temperature. The resulting precipitate was collected, washed with water, dried and then purified by preparative HPLC using acetonitrile and ammonium acetate buffer (25 / 75-95 / 5) to give the title compound (193 mg, 69 %).
¹ H-NMR (500 MHz, CD ₃ OD) δ (ppm): 0.92-1.02 (m, 2H), 1.12-1.30 (m, 3H), 1.50-1.60 ( m, 1H), 1.62-1.78 (m, 5H), 3.15 (d, J = 7.0 Hz, 2H), 6.19 (s, 2H), 6.96 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 7.0 Hz, 1H), 7.60-7.66 (m, 2H), 7.73 (d, J = 0.9 Hz, 1H), 7.84 (d, J = 7.0 Hz, 1H), 7.94 (d, J = 0.9 Hz, 1H), 8.19-8.24 (m, 1H), 8.43-8.48 (M, 1H), 9.12 (d, J = 8.9 Hz, 1H); MS (ESI): (M + H) ⁺ 485.15.

実施例１Ｄで製造した、６−メトキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル（０.５ｇ、１.２ｍｍｏｌ）及びシクロヘキサンメチルアミン （０.４１ｇ、３.６ｍｍｏｌ）のＤＭＦ（３ｍｌ）溶液を、８０℃で４０分間 加熱した。溶液を減圧下で蒸発させ、そして残留物をジクロロメタンに溶解した。水（５０ｍｌ）及び２ＮのＨＣｌ（水溶液）（１３ｍｌ）を加えた後、有機相を分離し、ＮａＨＣＯ₃ （飽和水溶液）及びブラインで洗浄し、次いで、乾燥し、減圧下で蒸発させた。残留物を、溶離液としてアセトニトリル及び酢酸アンモニウム緩衝液（３０／７０〜９５／５）を用いた分取型ＨＰＬＣで精製し、Ｎ−（シクロヘキシルメチル）−６−メトキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（５１７ｍｇ、８６％）を得た。
¹Ｈ−ＮＭＲ（６００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：０.９３−１.０２（ｍ，２Ｈ），１.０９−１.２７（ｍ，３Ｈ），１.５０−１.５８（ｍ，１Ｈ），１.６２−１.７８（ｍ，５Ｈ），３.２２（ｔ，Ｊ＝６.７Ｈｚ，２Ｈ），３.９４（ｓ，３Ｈ），６.０４（ｓ，２Ｈ），７.０１（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），７.３６（ｓ，１Ｈ），７.４１（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.５３−７.６０（ｍ，２Ｈ），７.６６（ｓ，１Ｈ），７.８３（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.９８（ｄ，Ｊ＝７.８Ｈｚ，１Ｈ），８.２３（ｔ，Ｊ＝６.５Ｈｚ，１Ｈ），８.５３（ｄ，Ｊ＝８.５Ｈｚ，１Ｈ），９.３１（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），１２.６２（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４９９.１２。 Example 1C
N- (cyclohexylmethyl) -6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide

Methyl 6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxylate prepared in Example 1D (0.5 g) 1.2 mmol) and cyclohexanemethylamine (0.41 g, 3.6 mmol) in DMF (3 ml) were heated at 80 ° C. for 40 min. The solution was evaporated under reduced pressure and the residue was dissolved in dichloromethane. After adding water (50 ml) and 2N HCl (aq) (13 ml), the organic phase was separated and washed with NaHCO ₃ (sat. Aq.) And brine, then dried and evaporated under reduced pressure. The residue was purified by preparative HPLC using acetonitrile and ammonium acetate buffer (30/70 to 95/5) as eluent, and N- (cyclohexylmethyl) -6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide (517 mg, 86%) was obtained.
¹ H-NMR (600 MHz, CDCl ₃ ) δ (ppm): 0.93-1.02 (m, 2H), 1.09-1.27 (m, 3H), 1.50-1.58 (m , 1H), 1.62-1.78 (m, 5H), 3.22 (t, J = 6.7 Hz, 2H), 3.94 (s, 3H), 6.04 (s, 2H), 7.01 (d, J = 9.1 Hz, 1H), 7.36 (s, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.53-7.60 (m, 2H) ), 7.66 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 8.23 (t, J = 6) .5 Hz, 1 H), 8.53 (d, J = 8.5 Hz, 1 H), 9.31 (d, J = 9.1 Hz, 1 H), 12.62 (s, 1 H); MS (ESI): (M + H) ^<+ > 499.12.

実施例１Ｅで製造した、６−メトキシ−３−［（４−メチル−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチル（１.８ｇ、５.１４ｍｍｏｌ） のＣＣｌ₄（１００ ｍｌ）中の混合物に、Ｎ−ブロモスクシンイミド（０.９６ｇ、５.３９ｍｍｏｌ）及び過酸化ベンゾイル（０.１２５ｇ、０.５１ｍｍｏｌ）を加えた。反応混合物を窒素雰囲気下で、１.５時間還流させた。ＤＭＦ（２.５ｍｌ）及び１，２，３−トリアゾール（２.９８ｍｌ、５１.４ｍｍｏｌ）を加え、そして、反応混合物を終夜還流した。溶媒を除去した後、残留物を冷水中に懸濁させた。生成した沈澱物を集め、水で洗浄し、風乾し、溶離液として、初めにＣＨ₂Ｃｌ₂、次いでＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／１）を用いたシリカゲル上でのカラムクロマトグラフィーで精製し、６−メトキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１ ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル（１.５５ｇ、７２％）を得た。
ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺４１８.１３。 Example 1D
6-Methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxylate methyl

Methyl 6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate (1.8 g, 5.14 mmol) prepared in Example 1E in CCl ₄ (100 ml). To the mixture was added N-bromosuccinimide (0.96 g, 5.39 mmol) and benzoyl peroxide (0.125 g, 0.51 mmol). The reaction mixture was refluxed for 1.5 hours under a nitrogen atmosphere. DMF (2.5 ml) and 1,2,3-triazole (2.98 ml, 51.4 mmol) were added and the reaction mixture was refluxed overnight. After removing the solvent, the residue was suspended in cold water. The resulting precipitate was collected, washed with water, air dried and purified by column chromatography on silica gel using initially CH ₂ Cl ₂ and then CH ₂ Cl ₂ / MeOH (100/1) as eluent. 6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1 naphthoyl] amino} pyridine-2-carboxylate (1.55 g, 72%) It was.
MS (ESI) (M + H) ^<+ > 418.13.

実施例１Ｆで製造した、３−アミノ−６−メトキシ−ピリジン−２−カルボン酸（１.７８ｇ、１０.６ｍｍｏｌ）の無水ＤＭＦ（３０ｍｌ）中の混合物に、ＤＩＰＥＡ（１１.０７ｍｌ、６３.６ｍｍｏｌ）及び４−メチル−１−ナフタレンカルボニルクロリド（２.６５ｇ、１２.９５ｍｍｏｌ）を窒素雰囲気下で加えた。室温で１時間、次いで５０℃で１時間撹拌した後、Ｋ₂ＣＯ₃（２.２ｇ、１５.９ｍｍｏｌ）を反応混合物に加え、次いで、室温でＭｅＩ（３.３ｍｌ、５３ｍｍｏｌ）を小分けして加えた。終夜撹拌した後、反応混合物を濃縮し、そして残留物を水中に懸濁させ、結晶を濾過し、水、エタノールで洗浄し、風乾した。粗生成物（２.７ｇ）を酢酸エチル／メタノール中に懸濁し、そして結晶を濾過し、メタノール、エーテルで洗浄し、風乾し、６−メトキシ−３−［（４−メチル−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチル（２ｇ、５４％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ ３５１.１０。 Example 1E
Methyl 6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate

To a mixture of 3-amino-6-methoxy-pyridine-2-carboxylic acid prepared in Example 1F (1.78 g, 10.6 mmol) in anhydrous DMF (30 ml) was added DIPEA (11.07 ml, 63.6 mmol). ) And 4-methyl-1-naphthalenecarbonyl chloride (2.65 g, 12.95 mmol) were added under a nitrogen atmosphere. After stirring at room temperature for 1 hour and then at 50 ° C. for 1 hour, K ₂ CO ₃ (2.2 g, 15.9 mmol) was added to the reaction mixture and then MeI (3.3 ml, 53 mmol) was aliquoted at room temperature. added. After stirring overnight, the reaction mixture was concentrated and the residue was suspended in water, the crystals were filtered, washed with water, ethanol and air dried. The crude product (2.7 g) was suspended in ethyl acetate / methanol and the crystals were filtered, washed with methanol, ether, air dried and 6-methoxy-3-[(4-methyl-1-naphthoyl). Methyl amino] pyridine-2-carboxylate (2 g, 54%) was obtained.
MS (ESI): (M + H) ^<+ > 351.10.

Goldbergら [Besly; Goldberg; JCSOA9; J. Chem. Soc.; 2448, 2455]の手順に従って得られた、３−（アセチルアミノ）−６−メトキシピリジン−２−カルボン酸（７.９６ｇ、３７.８８ｍｍｏｌ）を、２.５ＮのＮａＯＨ（飽和水溶液）（８０ｍｌ）中で、８０分間還流した。溶液を０℃で、４ＮのＨＣｌ（水溶液）を用いてｐＨ４に調節した。生成した沈澱物を集め、冷水で洗浄し、風乾し、３−アミノ−６−メトキシ−ピリジン−２−カルボン酸（５.６５ｇ、８９％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ １６９.１４。 Example 1F
3-Amino-6-methoxy-pyridine-2-carboxylic acid

3- (acetylamino) -6-methoxypyridine-2-carboxylic acid (7.96 g, 37. 88 mmol) was refluxed in 2.5 N NaOH (saturated aqueous solution) (80 ml) for 80 minutes. The solution was adjusted to pH 4 with 4N HCl (aq) at 0 ° C. The resulting precipitate was collected, washed with cold water and air dried to give 3-amino-6-methoxy-pyridine-2-carboxylic acid (5.65 g, 89%).
MS (ESI): (M + H) ^<+ > 169.14.

Example 2
[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) Oxy] methyl acetate

実施例１Ａに記載された手順に従い、実施例２Ｂで製造された、Ｎ−（シクロブチルメチル）−６−ヒドロキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（３００ｍｇ、０.６６ｍｍｏｌ）及びブロモ酢酸メチル（３０２ｍｇ、１.９７ｍｍｏｌ）を用い、溶離液として、ＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／１.５）を用いたシリカゲル上でのカラムクロマトグラフィーで精製した後、標題の化合物（２５０ｍｇ、７２％）を得た。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６０−１.８０（ｍ，２Ｈ），１.８１−２.０（ｍ，２Ｈ），２.０１−２.２０（ｍ，２Ｈ），２.４７−２.６５（ｍ，１Ｈ），３.３８（ｔ，Ｊ＝６.９Ｈｚ，２Ｈ），３.７４（ｓ，３Ｈ），４.７７（ｓ，２Ｈ），６.０４（ｓ，２Ｈ），７.１４（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），７.３８（ｓ，１Ｈ），７.４０（ｄ，Ｊ＝７.４Ｈｚ，１Ｈ），７.５１−７.６２（ｍ，２Ｈ），７.６６（ｓ，１Ｈ），７.７９−７.９２（ｍ，２Ｈ），７.９４−８.０３（ｍ，１Ｈ），８.４７−８.５６（ｍ，１Ｈ），９.３８（ｄ，Ｊ＝９.２Ｈｚ，１Ｈ），１２.６４（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５２９.０４。 Example 2A
[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) Oxy] methyl acetate

N- (cyclobutylmethyl) -6-hydroxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) prepared in Example 2B according to the procedure described in Example 1A ) -1-Naphthoyl] amino} pyridine-2-carboxamide (300 mg, 0.66 mmol) and methyl bromoacetate (302 mg, 1.97 mmol) and CH ₂ Cl _{2 /} MeOH (100 / 1.5) as eluent. The title compound (250 mg, 72%) was obtained after purification by column chromatography on silica gel using
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.60-1.80 (m, 2H), 1.81-2.0 (m, 2H), 2.01-2.20 (m, 2H) ), 2.47-2.65 (m, 1H), 3.38 (t, J = 6.9 Hz, 2H), 3.74 (s, 3H), 4.77 (s, 2H), 6. 04 (s, 2H), 7.14 (d, J = 9.1 Hz, 1H), 7.38 (s, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.51- 7.62 (m, 2H), 7.66 (s, 1H), 7.79-7.92 (m, 2H), 7.94-8.03 (m, 1H), 8.47-8. 56 (m, 1H), 9.38 (d, J = 9.2 Hz, 1H), 12.64 (s, 1H); MS (ESI): (M + H) ⁺ 529.04.

Ｎ−（シクロブチルメチル）−６−メトキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（３００ｍｇ、０.６４ｍｍｏｌ）及びピリジン塩酸塩（７ ｇ、６０.５７ｍｍｏｌ）の混合物を、１５０℃で３０分間加熱した。室温で水を加えた。生成した沈澱物を集め、水で洗浄し、乾燥し、アセトニトリル及び酢酸アンモニウム緩衝液（２０／８０〜９５／５）を用いた分取型ＨＰＬＣで精製し、標題の化合物（２２３ｍｇ、７７％）を得た。
¹Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：１.６６−１８１（ｍ，２Ｈ），１.８２−１.９４（ｍ，２Ｈ），２.０−２.１４（ｍ，２Ｈ），２.４７−２.６５（ｍ，１Ｈ），３.３−２.３７（ｍ，２Ｈ），６.１９（ｓ，２Ｈ），６.９０（ｄ，Ｊ＝９.２４Ｈｚ，１Ｈ），７.４６（ｄ，Ｊ＝７.２２Ｈｚ，１Ｈ），７.５７−７.６８（ｍ，２Ｈ），７.７３（ｓ，１Ｈ），７.８４（ｄ，Ｊ＝７.３９Ｈｚ，１Ｈ）），７.９４（ｓ，１Ｈ），８.１６−８.２６（ｍ，１Ｈ），８.４１−８.５０（ｍ，１Ｈ），９.１１（ｄ，Ｊ＝９.０６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺３５７。 Example 2B
N- (cyclobutylmethyl) -6-hydroxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide

N- (cyclobutylmethyl) -6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide (300 mg, 0. 64 mmol) and pyridine hydrochloride (7 g, 60.57 mmol) were heated at 150 ° C. for 30 min. Water was added at room temperature. The resulting precipitate was collected, washed with water, dried and purified by preparative HPLC using acetonitrile and ammonium acetate buffer (20 / 80-95 / 5) to give the title compound (223 mg, 77%) Got.
¹ H-NMR (300 MHz, CD ₃ OD) δ (ppm): 1.66-181 (m, 2H), 1.82-1.94 (m, 2H), 2.0-2.14 (m, 2H), 2.47-2.65 (m, 1H), 3.3-2.37 (m, 2H), 6.19 (s, 2H), 6.90 (d, J = 9.24 Hz, 1H), 7.46 (d, J = 7.22 Hz, 1H), 7.57-7.68 (m, 2H), 7.73 (s, 1H), 7.84 (d, J = 7. 39 Hz, 1H)), 7.94 (s, 1H), 8.16-8.26 (m, 1H), 8.41-8.50 (m, 1H), 9.11 (d, J = 9 .06 Hz, 1H); MS (ESI): (M + H) ⁺ 357.

６−メトキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル（１ｇ、 ２.４ｍｍｏｌ、実施例１Ｄを参照）及びシクロブチルメチルアミン（４９０ ｍｇ、５.７５ｍｍｏｌ）のＤＭＦ（７ｍｌ）溶液を、８０℃で１４０分間加熱した。更に、シクロブチルメチルアミン（２４０ｍｇ、２.８２ｍｍｏｌ）を加え、反応混合物を８０℃で更に９０分間加熱した。溶液を減圧下で蒸発させ、そして残留物を、溶離液としてアセトニトリル及び酢酸アンモニウム緩衝液（２０／８０〜９５／５）を用いた分取型ＨＰＬＣで精製し、６−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（９８０ｍｇ、８７％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ ４７１.０４。 Example 2C
6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2- Carboxamide

Methyl 6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxylate (1 g, 2.4 mmol, Example 1D) And a solution of cyclobutylmethylamine (490 mg, 5.75 mmol) in DMF (7 ml) was heated at 80 ° C. for 140 minutes. Further cyclobutylmethylamine (240 mg, 2.82 mmol) was added and the reaction mixture was heated at 80 ° C. for an additional 90 minutes. The solution was evaporated under reduced pressure and the residue was purified by preparative HPLC using acetonitrile and ammonium acetate buffer (20 / 80-95 / 5) as eluent, and 6-methoxy-N- (tetrahydro -2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide (980 mg, 87%). Obtained.
MS (ESI): (M + H) ^<+ > 471.04.

実施例２Ａで製造した［（６−｛［（シクロブチルメチル）アミノ］カルボニル｝−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−イル）オキシ］酢酸メチル（１５０ｍｇ、 ０.２８ｍｍｏｌ）のメタノール／エタノール（１０ｍｌ、１／１）中の懸濁液に、ＮａＯＨ（３３ｍｇ：水０.６ｍｌに溶解）の溶液を加えた。反応混合物を室温で４５分間撹拌し、次いで酢酸（１５０ｍｌ）を加えて、クエンチした。溶液を減圧下で蒸発させ、そして残留物をジクロロメタンに溶解し、水、ブラインで洗浄し、次いで減圧下で蒸発させ、標題の化合物（１３９ｍｇ、９５％）を得た。
¹ＨＮＭＲ（６００ＭＨｚ，ＣＤ₃ＣＯＤ）δ（ｐｐｍ）：１.７２−１.８０（ｍ，２Ｈ），１.８４−１.９５（ｍ，２Ｈ），２.０４−２.１２（ｍ，２Ｈ），２.５３−２.６２（ｍ，１Ｈ），３.３３−３.３６（ｍ，２Ｈ），４.８９（ｓ，２Ｈ），６.１９（ｓ，２Ｈ），７.１９（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），７.４５（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.５９−７.６５（ｍ，２Ｈ），７.７３（ｓ，１Ｈ），７.８５（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.９４（ｓ，１Ｈ），８.１８−８.２４（ｍ，１Ｈ），８.３８（ｔ，Ｊ＝５.５Ｈｚ，１Ｈ），８.４４−８.４９（ｍ，１Ｈ），９.２５（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５１５。 Example 3
[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) Oxy] acetic acid

[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} prepared in Example 2A To a suspension of methyl pyridin-2-yl) oxy] acetate (150 mg, 0.28 mmol) in methanol / ethanol (10 ml, 1/1) was added a solution of NaOH (33 mg: dissolved in 0.6 ml water). It was. The reaction mixture was stirred at room temperature for 45 minutes and then quenched by the addition of acetic acid (150 ml). The solution was evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with water, brine and then evaporated under reduced pressure to give the title compound (139 mg, 95%).
¹ HNMR (600 MHz, CD ₃ COD) δ (ppm): 1.72-1.80 (m, 2H), 1.84-1.95 (m, 2H), 2.04-2.12 (m, 2H), 2.55-2.62 (m, 1H), 3.33-3.36 (m, 2H), 4.89 (s, 2H), 6.19 (s, 2H), 7.19 (D, J = 9.1 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.59-7.65 (m, 2H), 7.73 (s, 1H), 7 .85 (d, J = 7.3 Hz, 1H), 7.94 (s, 1H), 8.18-8.24 (m, 1H), 8.38 (t, J = 5.5 Hz, 1H) , 8.44-8.49 (m, 1H), 9.25 (d, J = 9.1 Hz, 1H); MS (ESI): (M + H) ⁺ 515.

実施例３で製造した［（６−｛［（シクロブチルメチル）アミノ］カルボニル｝−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−イル）オキシ］酢酸（５０ｍｇ、０.０９７ｍｍｏｌ）の無水ＤＭＦ（２ ｍｌ）溶液に、ＴＢＴＵ（４７ｍｇ、０.１５ｍｍｏｌ）、ＤＩＰＥＡ（２５ｍｇ、０.１９ ｍｍｏｌ）及び塩化アンモニウム（３０ｍｇ、０.５６ｍｍｏｌ）を窒素雰囲気下で加えた。反応混合物を室温で１時間撹拌した。水を加え、生成した沈澱物を集め、水で洗浄し、そして風乾した。固体をジクロロメタン／メタノールに溶解し、濾過した。溶液を減圧下で蒸発させ、残留物をエーテル中で懸濁させた。固体を集め、エーテルで洗浄し、減圧下で乾燥して、標題の化合物（４９ｍｇ、９８％）を得た。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６９−１.８１（ｍ，２Ｈ），１.８２−２.０（ｍ，２Ｈ），２.０３−２.１８（ｍ，２Ｈ），２.５０−２.６５（ｍ，１Ｈ），３.４０（ｔ，Ｊ＝６.９Ｈｚ），４.７４（ｓ，２Ｈ），５.４７（ｂｒｓ，１Ｈ），６.０６（ｓ，２Ｈ），６.２２（ｂｒｓ，１Ｈ），７.１３（ｄ，Ｊ＝９.２Ｈｚ，１Ｈ），７.４０（ｓ，１Ｈ），７.４４（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.５３−７.６５（ｍ，２Ｈ），７.６９（ｓ，１Ｈ），７.８５（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.９５−８.０８（ｍ，２Ｈ），８.５０−８.５９（ｍ，１Ｈ），９.４３（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），１２.７０（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５１４。 Example 4
6- (2-Amino-2-oxoethoxy) -N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-carboxamide

[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} prepared in Example 3 To a solution of pyridin-2-yl) oxy] acetic acid (50 mg, 0.097 mmol) in anhydrous DMF (2 ml), TBTU (47 mg, 0.15 mmol), DIPEA (25 mg, 0.19 mmol) and ammonium chloride (30 mg, 0.56 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. Water was added and the resulting precipitate was collected, washed with water and air dried. The solid was dissolved in dichloromethane / methanol and filtered. The solution was evaporated under reduced pressure and the residue was suspended in ether. The solid was collected, washed with ether and dried under reduced pressure to give the title compound (49 mg, 98%).
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.69-1.81 (m, 2H), 1.82-2.0 (m, 2H), 2.03-2.18 (m, 2H) ), 2.50-2.65 (m, 1H), 3.40 (t, J = 6.9 Hz), 4.74 (s, 2H), 5.47 (brs, 1H), 6.06 ( s, 2H), 6.22 (brs, 1H), 7.13 (d, J = 9.2 Hz, 1H), 7.40 (s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.53-7.65 (m, 2H), 7.69 (s, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.95-8.08 (m, 2H), 8.50-8.59 (m, 1H), 9.43 (d, J = 9.1 Hz, 1H), 12.70 (s, 1H); MS (ESI): (M + H) ⁺ 514 .

実施例４に記載された手順に従い、実施例３で製造した［（６−｛［（シクロブチルメチル）アミノ］カルボニル｝−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−イル）オキシ］酢酸（５０ｍｇ、０.０９７ｍｍｏｌ）及びメチルアミン塩酸塩（３２ｍｇ、０.４７ｍｍｏｌ）を用いて処理した後、標題の化合物（５１ｍｇ、９９％）を得た。
¹ＨＮＭＲ（６００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６０−１.７９（ｍ，２Ｈ），１.８１−１.９６（ｍ，２Ｈ）.２０２−２.１３（ｍ，２Ｈ），２.５２−２.６４（ｍ，１Ｈ），２.８６（ｂｒｓ，３Ｈ），３.３２−３.４２（ｍ，２Ｈ），４.７３（ｓ，２Ｈ），６.０６（ｓ，２Ｈ），６.２９（ｂｒｓ，１Ｈ），７.０９（ｄ，Ｊ＝８.７Ｈｚ，１Ｈ），７.３７（ｓ，１Ｈ），７.４２（ｄ，Ｊ＝６.２Ｈｚ，１Ｈ），７.５２−７.６２（ｍ，２Ｈ），７.６７（ｓ，１Ｈ），７.８３（ｄ，Ｊ＝６.７Ｈｚ，１Ｈ），７.９３−８.０６（ｍ，２Ｈ），８.５２（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），９.３８（ｄ，Ｊ＝８.６Ｈｚ，１Ｈ），１２.７０（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５２８。 Example 5
N- (cyclobutylmethyl) -6- [2- (methylamino) -2-oxoethoxy] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] Amino} pyridine-2-carboxamide

[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole-1) prepared in Example 3 according to the procedure described in Example 4 After treatment with -ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy] acetic acid (50 mg, 0.097 mmol) and methylamine hydrochloride (32 mg, 0.47 mmol), the title compound (51 mg 99%).
¹ HNMR (600 MHz, CDCl ₃ ) δ (ppm): 1.60-1.79 (m, 2H), 1.81-1.96 (m, 2H). 202-2.13 (m, 2H), 2.52-2.64 (m, 1H), 2.86 (brs, 3H), 3.32-3.42 (m, 2H), 4.73 (s, 2H), 6.06 (s, 2H), 6.29 (brs, 1H), 7.09 (d, J = 8.7 Hz, 1H), 7.37 (s, 1H), 7.42 (d, J = 6.2 Hz, 1H) 7.52-7.62 (m, 2H), 7.67 (s, 1H), 7.83 (d, J = 6.7 Hz, 1H), 7.93-8.06 (m, 2H) 8.52 (d, J = 7.2 Hz, 1H), 9.38 (d, J = 8.6 Hz, 1H), 12.70 (s, 1H); MS (ESI): (M + H) ⁺ 528 .

実施例４に記載された手順に従い、実施例３で製造した［（６−｛［（シクロブチルメチル）アミノ］カルボニル｝−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−イル）オキシ］酢酸（１９ｍｇ、０.０３７ｍｍｏｌ）及びジメチルアミン塩酸塩（１２ｍｇ、０.１５ｍｍｏｌ）を用いて処理した後、標題の化合物（１８ｍｇ， ９０％）を得た。
¹ＨＮＭＲ（６００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.７０−１.８０（ｍ，２Ｈ），１.８２−１.９５（ｍ，２Ｈ），２.０３−２.１２（ｍ，２Ｈ），２.５８−２.６８（ｍ，１Ｈ），２.８８（ｓ，３Ｈ），３.０７（ｓ，３Ｈ），３.３９（ｔ，Ｊ＝６.３Ｈｚ，２Ｈ），４.８２（ｓ，２Ｈ），６.０４（ｓ，２Ｈ），７.０６（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），７.３７（ｓ，１Ｈ），７.４１（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.５３−７.６０（ｍ，２Ｈ），７.６７（ｓ，１Ｈ），７.８３（ｄ，Ｊ＝７.０Ｈｚ，１Ｈ），７.９７（ｄ，Ｊ＝８.０Ｈｚ，１Ｈ），８.４１−８.４４（ｍ，１Ｈ），８.５１（ｄ，Ｊ＝８.０Ｈｚ，１Ｈ），９.３４（ｄ，Ｊ＝９.０Ｈｚ，１Ｈ），１２.６８（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５４２.０２。 Example 6
N- (cyclobutylmethyl) -6- [2- (dimethylamino) -2-oxoethoxy] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] Amino} pyridine-2-carboxamide

[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole-1) prepared in Example 3 according to the procedure described in Example 4 After treatment with -ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy] acetic acid (19 mg, 0.037 mmol) and dimethylamine hydrochloride (12 mg, 0.15 mmol), the title compound (18 mg 90%).
¹ HNMR (600 MHz, CDCl ₃ ) δ (ppm): 1.70-1.80 (m, 2H), 1.82-1.95 (m, 2H), 2.03-2.12 (m, 2H) ), 2.58-2.68 (m, 1H), 2.88 (s, 3H), 3.07 (s, 3H), 3.39 (t, J = 6.3 Hz, 2H), 4. 82 (s, 2H), 6.04 (s, 2H), 7.06 (d, J = 9.1 Hz, 1H), 7.37 (s, 1H), 7.41 (d, J = 7. 2 Hz, 1H), 7.53-7.60 (m, 2H), 7.67 (s, 1H), 7.83 (d, J = 7.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1 H), 8.41-8.44 (m, 1 H), 8.51 (d, J = 8.0 Hz, 1 H), 9.34 (d, J = 9.0 Hz, 1 H), 12.68 (s, 1 H); MS (ESI): (M + H) ⁺ 542.02.

実施例４に記載された手順に従い、実施例３から得られた［（６−｛［（シクロブチルメチル）アミノ］カルボニル｝−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−イル）オキシ］酢酸（５０ｍｇ、０.０９７ｍｍｏｌ）及びエタノールアミン（１７ｍｇ、０.２８ｍｍｏｌ）を用いて処理した後、標題の化合物（５３ｍｇ、９８％）を得た。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６０−１.８２（ｍ，２Ｈ），１.８４−１.９８（ｍ，２Ｈ），２.０４−２.２０（ｍ，２Ｈ），２.５１−２.６７（ｍ，１Ｈ），３.３４−３.４４（ｍ，２Ｈ），３.４５−３.５４（ｍ，２Ｈ），３.６９−３.７７（ｍ，２Ｈ），４.７６（ｓ，２Ｈ），６.０６（ｓ，２Ｈ），６.６６−６.７７（ｍ，１Ｈ），７.１３（ｄ，Ｊ＝９.２Ｈｚ，１Ｈ），７.４０（ｓ，１Ｈ），７.４３（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.５５−７.６４（ｍ，２Ｈ），７.６９（ｓ，１Ｈ），７.８５（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.５５−７.６４（ｍ，２Ｈ），７.６９（ｓ，１Ｈ），７.８５（ｄ.Ｊ＝９.１Ｈｚ，１Ｈ），７.９５−８.０７（ｍ，２Ｈ），８.５０−８.５９（ｍ，１Ｈ），９.４２（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），１２.７０（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５５８。 Example 7
N- (cyclobutylmethyl) -6- {2-[(2-hydroxyethyl) amino] -2-oxoethoxy} -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide

[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole-) obtained from Example 3 according to the procedure described in Example 4) After treatment with 1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy] acetic acid (50 mg, 0.097 mmol) and ethanolamine (17 mg, 0.28 mmol), the title compound (53 mg, 98%) was obtained.
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.60-1.82 (m, 2H), 1.84-1.98 (m, 2H), 2.04-2.20 (m, 2H) ), 2.51-2.67 (m, 1H), 3.34-3.44 (m, 2H), 3.45-3.54 (m, 2H), 3.69-3.77 (m) , 2H), 4.76 (s, 2H), 6.06 (s, 2H), 6.66-6.77 (m, 1H), 7.13 (d, J = 9.2 Hz, 1H), 7.40 (s, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.55-7.64 (m, 2H), 7.69 (s, 1H), 7.85 ( d, J = 7.2 Hz, 1H), 7.55-7.64 (m, 2H), 7.69 (s, 1H), 7.85 (d.J = 9.1 Hz, 1H), 7. 95-8.07 (m, 2H), 8.50-8.59 (m, 1H), 9.42 (d, J = 9. Hz, 1H), 12.70 (s , 1H); MS (ESI) :( M + H) + 558.

実施例１Ａに記載された方法に従い、実施例２Ｂで製造したＮ−（シクロブチルメチル）−６−ヒドロキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（５０ｍｇ、０.１１ｍｍｏｌ）、エタンスルホニルクロリド（４２ｍｇ、０.３３ｍｍｏｌ）を用い、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／１.５）を用いたシリカゲル上でのカラムクロマトグラフィーで精製した後、標題の化合物（５０ｍｇ、８３％）を得た。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６２（ｔ，Ｊ＝７.４Ｈｚ，３Ｈ），１.６６−２.０１（ｍ，４Ｈ），２.０２−２.１８（ｍ，２Ｈ），２.４９−２.６６（ｍ，１Ｈ），３.３５−３.５２（ｍ，４Ｈ），６.０７（ｓ，２Ｈ），７.３４−７.４５（ｍ，３Ｈ），７.５４−７.６６（ｍ，２Ｈ），７.６９（ｓ，１Ｈ），７.８５（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.９２−８.０８（ｍ，２Ｈ），８.４８−８.５９（ｍ，１Ｈ），９.５７（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），１２.８１（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５４９.０６。 Example 8
Ethanesulfonic acid 6-{[(cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl

N- (Cyclobutylmethyl) -6-hydroxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl)-prepared in Example 2B according to the method described in Example 1A 1-naphthoyl] amino} pyridine-2-carboxamide (50 mg, 0.11 mmol), ethanesulfonyl chloride (42 mg, 0.33 mmol) and CH ₂ Cl _{2 /} MeOH (100 / 1.5) as eluent. After purification by column chromatography on silica gel, the title compound (50 mg, 83%) was obtained.
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.62 (t, J = 7.4 Hz, 3H), 1.66-2.01 (m, 4H), 2.02-2.18 (m , 2H), 2.49-2.66 (m, 1H), 3.35-3.52 (m, 4H), 6.07 (s, 2H), 7.34-7.45 (m, 3H) ), 7.54-7.66 (m, 2H), 7.69 (s, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.92-8.08 (m, 2H) ), 8.48-8.59 (m, 1H), 9.57 (d, J = 9.1 Hz, 1H), 12.81 (s, 1H); MS (ESI): (M + H) ⁺ 549. 06.

実施例１Ａに記載された方法に従い、実施例２Ｂで製造したＮ−（シクロブチルメチル）−６−ヒドロキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（３７ｍｇ、０.０８１ｍｍｏｌ）及び３，３，３−トリフルオロプロピルスルホニルクロリド（３２ｍｇ、０.１６ｍｍｏｌ）を用い、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／１.５）を用いたシリカゲル上でのカラムクロマトグラフィーで精製した後、標題の化合物（３０ｍｇ、６０％）を得た。
¹ＨＮＭＲ（６００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.７０−１.７２（ｍ，２Ｈ），１.８５−１.９７（ｍ，２Ｈ），２.０５−２.１４（ｍ，２Ｈ），２.５１−２.６０（ｍ，１Ｈ），２.８８−２.９８（ｍ，２Ｈ），３.３９−３.４５（ｍ，２Ｈ），３.６６−３.７２（ｍ，２Ｈ），６.０７（ｓ，２Ｈ），７.３９−７.４５（ｍ，３Ｈ），７.５８−７.６５（ｍ，２Ｈ），７.７０（ｓ，１Ｈ），７.８０−７.９０（ｍ，２Ｈ），８.０１−８.０８（ｍ，１Ｈ），８.５２−８.５８（ｍ，１Ｈ），９.６２（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），１２.８８（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺６１６.９９。 Example 9
3,3,3-trifluoropropane-1-sulfonic acid 6-{[(cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl)- 1-naphthoyl] amino} pyridin-2-yl

N- (cyclobutylmethyl) -6-hydroxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl)-prepared in Example 2B according to the method described in Example 1A 1-naphthoyl] amino} pyridine-2-carboxamide (37 mg, 0.081 mmol) and 3,3,3-trifluoropropylsulfonyl chloride (32 mg, 0.16 mmol) with CH ₂ Cl ₂ / MeOH (eluent) After purification by column chromatography on silica gel using 100 / 1.5), the title compound (30 mg, 60%) was obtained.
¹ HNMR (600 MHz, CDCl ₃ ) δ (ppm): 1.70 to 1.72 (m, 2H), 1.85 to 1.97 (m, 2H), 2.05 to 2.14 (m, 2H) ), 2.51-2.60 (m, 1H), 2.88-2.98 (m, 2H), 3.39-3.45 (m, 2H), 3.66-3.72 (m) , 2H), 6.07 (s, 2H), 7.39-7.45 (m, 3H), 7.58-7.65 (m, 2H), 7.70 (s, 1H), 7. 80-7.90 (m, 2H), 8.01-8.08 (m, 1H), 8.52-8.58 (m, 1H), 9.62 (d, J = 9.1 Hz, 1H ), 12.88 (s, 1H); MS (ESI): (M + H) ⁺ 616.99.

Example 10
3,3,3-trifluoropropane-1-sulfonic acid 6-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole -1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl

実施例１Ａに記載された方法に従い、実施例１０Ｂで製造した６−ヒドロキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（５０ｍｇ、０.１０３ｍｍｏｌ）、及び３，３，３−トリフルオロプロピルスルホニルクロリド（４０ｍｇ、０.２１ｍｍｏｌ）を用い、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／１.５）を用いたシリカゲル上でのカラムクロマトグラフィーで精製した後、標題の化合物（２３ｍｇ、３５％）を得た。
¹ＨＮＭＲ（６００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.３４−１.４０（ｍ，２Ｈ），１.６０−１.６６（ｍ，２Ｈ），１.７８−１.８８（ｍ，１Ｈ），２.８８−２.９８（ｍ，２Ｈ），３.２８−３.４０（ｍ，４Ｈ），３.６５−３.７１（ｍ，２Ｈ），３.９５−４.０１（ｍ，２Ｈ），６.０８（ｓ，２Ｈ），７.４０−７.４５（ｍ，３Ｈ），７.５９−７.６６（ｍ，２Ｈ），７.７１（ｓ，１Ｈ），７.８６（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.９４−７.９９（ｍ，１Ｈ），８.０２−８.０８（ｍ，１Ｈ），８.５２−８.５７（ｍ，１Ｈ），９.６４（ｄ，Ｊ＝９.０Ｈｚ，１Ｈ），１２.８１（ｓ，１Ｈ）；ＭＳ（ＥＳ
Ｉ）：（Ｍ＋Ｈ）⁺６４６.９９。 Example 10A
3,3,3-trifluoropropane-1-sulfonic acid 6-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole -1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl

6-Hydroxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazole) prepared in Example 10B according to the method described in Example 1A -1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide (50 mg, 0.103 mmol) and 3,3,3-trifluoropropylsulfonyl chloride (40 mg, 0.21 mmol) as the eluent. After purification by column chromatography on silica gel using CH ₂ Cl _{2 /} MeOH (100 / 1.5), the title compound (23 mg, 35%) was obtained.
¹ HNMR (600 MHz, CDCl ₃ ) δ (ppm): 1.34-1.40 (m, 2H), 1.60-1.66 (m, 2H), 1.78-1.88 (m, 1H) ), 2.88-2.98 (m, 2H), 3.28-3.40 (m, 4H), 3.65-3.71 (m, 2H), 3.95-4.01 (m , 2H), 6.08 (s, 2H), 7.40-7.45 (m, 3H), 7.59-7.66 (m, 2H), 7.71 (s, 1H), 7. 86 (d, J = 7.3 Hz, 1H), 7.94-7.99 (m, 1H), 8.02-8.08 (m, 1H), 8.52-8.57 (m, 1H) ), 9.64 (d, J = 9.0 Hz, 1H), 12.81 (s, 1H); MS (ES
I): (M + H) ⁺ 646.99.

実施例１０Ｃで製造した６−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（１４５ｍｇ、０.３ｍｍｏｌ）、及びピリジン塩酸塩（３.８ｇ、３２.８８ｍｍｏｌ）の混合物を、１５０℃で２７分間加熱した。水を室温で加えた。生成した沈澱物を集め、水で洗浄し、乾燥し、そしてアセトニトリル及び酢酸アンモニウム緩衝液（２０／８０〜９５／５）を用いた分取型ＨＰＬＣで精製し、標題の化合物（１１３ｍｇ、８０％）を得た。
¹Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：１.２２−１.４０（ｍ，２Ｈ），１.５７−１.６９（ｍ，２Ｈ），１.７４−１.９２（ｍ，１Ｈ），３−２０−３.４２（ｍ，４Ｈ），３.８５−３.９６（ｍ，２Ｈ），６.２０（ｓ，２Ｈ），６.９６（ｄ，Ｊ＝９.０７Ｈｚ，１Ｈ），７.４６（ｄ，Ｊ＝７.３９Ｈｚ，１Ｈ），７.５８−７.６９（ｍ，２Ｈ），７.７４（ｓ，１Ｈ），７.８５（ｄ，Ｊ＝７.２２Ｈｚ，１Ｈ），７.９５（ｓ，１Ｈ），８.１８−８.２７（ｍ，１Ｈ），８.４１−８.５０（ｍ，１Ｈ），９.１２（ｄ，Ｊ＝９.０７Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４８７.１２。 Example 10B
6-hydroxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2- Carboxamide

6-Methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] prepared in Example 10C A mixture of amino} pyridine-2-carboxamide (145 mg, 0.3 mmol) and pyridine hydrochloride (3.8 g, 32.88 mmol) was heated at 150 ° C. for 27 minutes. Water was added at room temperature. The resulting precipitate was collected, washed with water, dried and purified by preparative HPLC using acetonitrile and ammonium acetate buffer (20 / 80-95 / 5) to give the title compound (113 mg, 80% )
¹ H-NMR (300 MHz, CD ₃ OD) δ (ppm): 1.22-1.40 (m, 2H), 1.57-1.69 (m, 2H), 1.74-1.92 ( m, 1H), 3-20-3.42 (m, 4H), 3.85-3.96 (m, 2H), 6.20 (s, 2H), 6.96 (d, J = 9. 07 Hz, 1H), 7.46 (d, J = 7.39 Hz, 1H), 7.58-7.69 (m, 2H), 7.74 (s, 1H), 7.85 (d, J = 7.22 Hz, 1H), 7.95 (s, 1H), 8.18-8.27 (m, 1H), 8.41-8.50 (m, 1H), 9.12 (d, J = 9.07 Hz, 1H); MS (ESI): (M + H) ⁺ 487.12.

実施例１Ｄから製造された６−メトキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル（５００ｍｇ、１.２ｍｍｏｌ）及び１−（テトラヒドロ−２Ｈ−ピラン−４−イル）メタンアミン（３９５ｍｇ、３.４２ｍｍｏｌ）のＤＭＦ（３ｍｌ）溶液を、８０℃で３時間加熱した。溶媒を減圧下で蒸発させ、そして残留物を、溶離液としてアセトニトリル及び酢酸アンモニウム緩衝液（２０／８０〜９０／１０）を用いた分取型ＨＰＬＣで精製し、６−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（４７３ｍｇ、７９％）を得た。
¹Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.３０−１.４１（ｍ，２Ｈ），１.６０−１.７０（ｍ，２Ｈ），１.８０−１.９４（ｍ，１Ｈ），３.２６−３.４３（ｍ，４Ｈ），３.９６（ｓ，３Ｈ），３.９６−４.０２（ｍ，２Ｈ），６.０６（ｓ，２Ｈ），７.０４（ｄ，Ｊ＝９.２３Ｈｚ，１Ｈ），７.３９（ｄ，Ｊ＝０.８４Ｈｚ，１Ｈ），７.４３（ｄ，Ｊ＝７.２２Ｈｚ，１Ｈ），７.５４−７.６４（ｍ，２Ｈ），７.６９（ｄ，Ｊ＝０.８４Ｈｚ，１Ｈ），７.８５（ｄ，Ｊ＝７.２１Ｈｚ，１Ｈ），７.９６−８.０４（ｍ，１Ｈ），８.２７（ｔ，Ｊ＝６.２１Ｈｚ，１Ｈ），８.５１−８.５９（ｍ，１Ｈ），９.３３（ｄ，Ｊ＝９.０７Ｈｚ，１Ｈ），１２.５５（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５０１.１２。 Example 10C
6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2- Carboxamide

Methyl 6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxylate prepared from Example 1D (500 mg, 1 .2 mmol) and 1- (tetrahydro-2H-pyran-4-yl) methanamine (395 mg, 3.42 mmol) in DMF (3 ml) were heated at 80 ° C. for 3 h. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC using acetonitrile and ammonium acetate buffer (20 / 80-90 / 10) as eluent to give 6-methoxy-N- (tetrahydro -2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide (473 mg, 79%). Obtained.
¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 1.30 to 1.41 (m, 2H), 1.60 to 1.70 (m, 2H), 1.80 to 1.94 (m , 1H), 3.26-3.43 (m, 4H), 3.96 (s, 3H), 3.96-4.02 (m, 2H), 6.06 (s, 2H), 7. 04 (d, J = 9.23 Hz, 1H), 7.39 (d, J = 0.84 Hz, 1H), 7.43 (d, J = 7.22 Hz, 1H), 7.54-7.64 (M, 2H), 7.69 (d, J = 0.84 Hz, 1H), 7.85 (d, J = 7.21 Hz, 1H), 7.96-8.04 (m, 1H), 8 .27 (t, J = 6.21 Hz, 1H), 8.51-8.59 (m, 1H), 9.33 (d, J = 9.07 Hz, 1H), 12.55 (s, 1H) MS (ESI): (M + H) ^<+ > 501.12.

実施例１Ａに記載された方法に従い、実施例１０Ｂ〜１０Ｃに記載した通りに製造した、６−ヒドロキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（５０ｍｇ、０.１０３ｍｍｏｌ）及びアセチルクロリド（１６ｍｇ、０.２１ｍｍｏｌ）を用い、
溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／１.５）を用いたシリカゲル上でのカラムクロマトグラフィーで精製した後、標題の化合物（５２ｍｇ、９６％）を得た。
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.３２−１.４（ｍ，２Ｈ），１.６２−１.６８（ｍ，２Ｈ），１.８０−１.９０（ｍ，１Ｈ），２.３９（ｓ，３Ｈ），３.２９（ｔ，Ｊ＝６.６Ｈｚ，２Ｈ），３.３８−３.４０（ｍ，２Ｈ），３.９５−４.０１（ｍ，２Ｈ），６.０８（ｓ，２Ｈ），７.３２（ｄ，Ｊ＝８.９Ｈｚ，１Ｈ），７.４２（ｄ，Ｊ＝１Ｈｚ，１Ｈ），７.４４（ｄ，Ｊ＝７.０Ｈｚ，１Ｈ），７.５８−７.６５（ｍ，２Ｈ），７.７１（ｄ，Ｊ＝１Ｈｚ，１Ｈ），７.８６（ｄ，Ｊ＝７.０Ｈｚ，１Ｈ），８.０１−８.０６（ｍ，１Ｈ），８.２１（ｔ，Ｊ＝６.６Ｈｚ，１Ｈ），８.５３−８.５７（ｍ，１Ｈ），９.５５（ｄ，Ｊ＝８.９Ｈｚ，１Ｈ），１２.８（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５２９.３２。 Example 11
Acetic acid 6-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-yl

6-Hydroxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H--, prepared as described in Examples 10B-10C according to the method described in Example 1A 1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide (50 mg, 0.103 mmol) and acetyl chloride (16 mg, 0.21 mmol),
After purification by column chromatography on silica gel using CH ₂ Cl _{2 /} MeOH (100 / 1.5) as eluent, the title compound (52 mg, 96%) was obtained.
¹ HNMR (500 MHz, CDCl ₃ ) δ (ppm): 1.32-1.4 (m, 2H), 1.62-1.68 (m, 2H), 1.80-1.90 (m, 1H) ), 2.39 (s, 3H), 3.29 (t, J = 6.6 Hz, 2H), 3.38-3.40 (m, 2H), 3.95-4.01 (m, 2H) ), 6.08 (s, 2H), 7.32 (d, J = 8.9 Hz, 1H), 7.42 (d, J = 1 Hz, 1H), 7.44 (d, J = 7.0 Hz) , 1H), 7.58-7.65 (m, 2H), 7.71 (d, J = 1 Hz, 1H), 7.86 (d, J = 7.0 Hz, 1H), 8.01-8 0.06 (m, 1H), 8.21 (t, J = 6.6 Hz, 1H), 8.53-8.57 (m, 1H), 9.55 (d, J = 8.9 Hz, 1H) , 12.8 (s, 1H); MS (ESI): (M + H) ⁺ 529.32.

実施例１Ａに記載された方法に従い、実施例２Ｂで製造したＮ−（シクロブチルメチル）−６−ヒドロキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（５０ｍｇ、０.１１ｍｍｏｌ）及び２−ブロモエタノール（４１ｍｇ、０.３３ｍｍｏｌ）を用いて分取型ＨＰＬＣで精製した後、標題の化合物（２７ｍｇ、４９％）及び副生成物Ｎ−（シクロブチルメチル）−６−［２−（２−ヒドロキシエトキシ）エトキシ］−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（１２Ａ参照）（１ ｍｇ、２％）を得た。
¹ＨＮＭＲ（６００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.７０−１.７８（ｍ，２Ｈ），１.８５−２.０（ｍ，２Ｈ），２.０５−２.１３（ｍ，２Ｈ），２.５２−２.６２（ｍ，１Ｈ），３.４０（ｔ，Ｊ＝６.４Ｈｚ，２Ｈ），４.０−４.０４（ｍ，２Ｈ），４.３９−４.４３（ｍ，２Ｈ），６.０６（ｓ，２Ｈ），７.０６（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），７.４０（ｓ，１Ｈ），７.４６（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.５４−７.６２（ｍ，２Ｈ），７.６９（ｓ，１Ｈ），７.８５（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.９９（ｄ，Ｊ＝７.６Ｈｚ，１Ｈ），８.０６−８.１２（ｍ，１Ｈ），８.５４（ｄ，Ｊ＝８.０Ｈｚ，１Ｈ），９.３４（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），１２.６４（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５０１。 Example 12
N- (cyclobutylmethyl) -6- (2-hydroxyethoxy) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide

N- (cyclobutylmethyl) -6-hydroxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl)-prepared in Example 2B according to the method described in Example 1A After purification by preparative HPLC using 1-naphthoyl] amino} pyridine-2-carboxamide (50 mg, 0.11 mmol) and 2-bromoethanol (41 mg, 0.33 mmol), the title compound (27 mg, 49% ) And by-product N- (cyclobutylmethyl) -6- [2- (2-hydroxyethoxy) ethoxy] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1 -Naphthoyl] amino} pyridine-2-carboxamide (see 12A) (1 mg, 2%) was obtained.
¹ HNMR (600 MHz, CDCl ₃ ) δ (ppm): 1.70-1.78 (m, 2H), 1.85-2.0 (m, 2H), 2.05-2.13 (m, 2H) ), 2.52-2.62 (m, 1H), 3.40 (t, J = 6.4 Hz, 2H), 4.0-4.04 (m, 2H), 4.39-4.43 (M, 2H), 6.06 (s, 2H), 7.06 (d, J = 9.1 Hz, 1H), 7.40 (s, 1H), 7.46 (d, J = 7.2 Hz) , 1H), 7.54-7.62 (m, 2H), 7.69 (s, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.9 (d, J = 7 .6 Hz, 1 H), 8.06-8.12 (m, 1 H), 8.54 (d, J = 8.0 Hz, 1 H), 9.34 (d, J = 9.1 Hz, 1 H), 12 .64 (s, 1H); MS (ESI): (M + H) ⁺ 501.

本化合物は、Ｎ−（シクロブチルメチル）−６−（２−ヒドロキシエトキシ）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（１ｍｇ、１％）（実施例１２を参照）の合成から、副生成物として単離した。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.７０−１.８０（ｍ，２Ｈ），１.８４−１.９７（ｍ，２Ｈ），２.０−２.１６（ｍ，２Ｈ），２.５２−２.６４（ｍ，１Ｈ），３.４２（ｔ，Ｊ＝６.４Ｈｚ，２Ｈ），３.６７−３.７２（ｍ，２Ｈ），３.７７−３.８３（ｍ，２Ｈ），３.８９−３.９４（ｍ，２Ｈ），４.４３−４.４９（ｍ，２Ｈ），６.０６（ｓ，２Ｈ），７.０７（ｄ，Ｊ＝９.２Ｈｚ，１Ｈ），７.３８（ｓ，１Ｈ），７.４３（ｄ，Ｊ＝７.６Ｈｚ，１Ｈ），７.５５−７.６５（ｍ，２Ｈ），７.６７（ｓ，１Ｈ），７.８５（ｄ，Ｊ＝７.４Ｈｚ，１Ｈ），７.９７−８.１４（ｍ，２Ｈ），８.５１−８.５８（ｍ，１Ｈ），９.３５（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），１２.６４（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５４５。 Example 12A
N- (cyclobutylmethyl) -6- [2- (2-hydroxyethoxy) ethoxy] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} Pyridine-2-carboxamide

This compound is N- (cyclobutylmethyl) -6- (2-hydroxyethoxy) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine. Isolated as a by-product from the synthesis of 2-carboxamide (1 mg, 1%) (see Example 12).
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.70-1.80 (m, 2H), 1.84-1.97 (m, 2H), 2.0-2.16 (m, 2H) ), 2.52-2.64 (m, 1H), 3.42 (t, J = 6.4 Hz, 2H), 3.67-3.72 (m, 2H), 3.77-3.83 (M, 2H), 3.89-3.94 (m, 2H), 4.43-4.49 (m, 2H), 6.06 (s, 2H), 7.07 (d, J = 9 .2 Hz, 1 H), 7.38 (s, 1 H), 7.43 (d, J = 7.6 Hz, 1 H), 7.55-7.65 (m, 2 H), 7.67 (s, 1 H ), 7.85 (d, J = 7.4 Hz, 1H), 7.97-8.14 (m, 2H), 8.51-8.58 (m, 1H), 9.35 (d, J = 9.1 Hz, 1 H), 12.64 (s, 1 H); MS (ESI): (M + H) ⁺ 545 .

実施例１Ａに記載された手順に従い、実施例１０Ｂ〜１０Ｃで記載された通りに製造した、６−ヒドロキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（５０ｍｇ、０.１０３ｍｍｏｌ）、及びベンジルブロミド（３５ｍｇ、０.２１ｍｍｏｌ）を用いて、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／２.５及び１００／１５）を用いたシリカゲル上でのカラムクロマトグラフィーで精製した後、標題の化合物（１２ｍｇ、２０％）、及び副生成物、３−ベンジル−１−［（４−｛［（６−（ベンジルオキシ）−２−｛［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］カルボニル｝ピリジン−３−イル）アミノ］カルボニル｝−１−ナフチル）メチル］−１Ｈ−１，２，３−トリアゾール−３−イウム （５２ｍｇ、６８％）を得た。
¹ＨＮＭＲ（６００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２２−１.３４（ｍ，２Ｈ），１.５１−１.５８（ｍ，２Ｈ），１.７０−１.８０（ｍ，１Ｈ），３.２１（ｔ，Ｊ＝６.７Ｈｚ，２Ｈ），３.２９−３.３６（ｍ，２Ｈ），３.９１−３.９７（ｍ，２Ｈ），５.３５（ｓ，２Ｈ），６.０４（ｓ，２Ｈ），７.１０（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），７.２８−７.３３（ｍ，１Ｈ），７.３５−７.４２（ｍ，６Ｈ），７.５３−７.６０（ｍ，２Ｈ），７.６６（ｓ，１Ｈ），７.８１（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.９５−８.０２（ｍ，２Ｈ），８.５２（ｄ，Ｊ＝８.５Ｈｚ，１Ｈ），９.３３（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），１２.５０（ｓ，１Ｈ）。ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５７７.１６。 Example 13
6- (Benzyloxy) -N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-carboxamide

6-Hydroxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H], prepared as described in Examples 10B-10C, following the procedure described in Example 1A. -1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide (50 mg, 0.103 mmol) and benzyl bromide (35 mg, 0.21 mmol) as eluent After purification by column chromatography on silica gel using CH ₂ Cl _{2 /} MeOH (100 / 2.5 and 100/15), the title compound (12 mg, 20%) and the by-product, 3-benzyl -1-[(4-{[(6- (benzyloxy) -2-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} pi 3-yl) amino] carbonyl} -1-naphthyl) was obtained methyl]-1H-1,2,3-triazol-3-ium (52mg, 68%).
¹ HNMR (600 MHz, CDCl ₃ ) δ (ppm): 1.22-1.34 (m, 2H), 1.51-1.58 (m, 2H), 1.70-1.80 (m, 1H ), 3.21 (t, J = 6.7 Hz, 2H), 3.29-3.36 (m, 2H), 3.91-3.97 (m, 2H), 5.35 (s, 2H) ), 6.04 (s, 2H), 7.10 (d, J = 9.1 Hz, 1H), 7.28-7.33 (m, 1H), 7.35-7.42 (m, 6H) ), 7.53-7.60 (m, 2H), 7.66 (s, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.95-8.02 (m, 2H) ), 8.52 (d, J = 8.5 Hz, 1H), 9.33 (d, J = 9.1 Hz, 1H), 12.50 (s, 1H). MS (ESI): (M + H) ^<+ > 577.16.

本化合物を、６−（ベンジルオキシ）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（５２ｍｇ、６８％）の合成（実施例１３を参照）からの副生成物として単離した。
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２０−１.３０（ｍ，２Ｈ），１.４８−１.５４（ｍ，２Ｈ），１.６９−１.７７（ｍ，１Ｈ），３.１７（ｔ，Ｊ＝６.
７Ｈｚ，２Ｈ），３.２７−３.３３（ｍ，２Ｈ），３.８８−３.９４（ｍ，２Ｈ），５.３４（ｓ，２Ｈ），５.９１（ｓ，２Ｈ），６.５３（ｓ，２Ｈ），７.０８（ｄ，Ｊ＝９.２Ｈｚ，１Ｈ），７.２６−７.４１（ｍ，８Ｈ），７.４６−７.４９（ｍ，２Ｈ），７.５４−７.５９（ｍ，２Ｈ），７.８２（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.９７（ｔ，Ｊ＝６.４Ｈｚ，１Ｈ），８.０４（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），８.１５（ｄ，Ｊ＝８.２Ｈｚ，１Ｈ），８.４７（ｄ，Ｊ＝７.６Ｈｚ，１Ｈ），９.２８（ｄ，Ｊ＝９.２Ｈｚ，１Ｈ），９.３７（ｓ，１Ｈ），９.５０（ｓ，１Ｈ），１２.５２（ｓ，１Ｈ）。 Example 13A
3-Benzyl-1-[(4-{[(6- (benzyloxy) -2-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} pyridin-3-yl) amino] carbonyl}- 1-naphthyl) methyl] -1H-1,2,3-triazole-3-ium

This compound was converted to 6- (benzyloxy) -N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl. Isolated as a by-product from the synthesis of amino} pyridine-2-carboxamide (52 mg, 68%) (see Example 13).
¹ HNMR (500 MHz, CDCl ₃ ) δ (ppm): 1.20-1.30 (m, 2H), 1.48-1.54 (m, 2H), 1.69-1.77 (m, 1H) ), 3.17 (t, J = 6.
7 Hz, 2H), 3.27-3.33 (m, 2H), 3.88-3.94 (m, 2H), 5.34 (s, 2H), 5.91 (s, 2H), 6 .53 (s, 2H), 7.08 (d, J = 9.2 Hz, 1H), 7.26-7.41 (m, 8H), 7.46-7.49 (m, 2H), 7 .54-7.59 (m, 2H), 7.82 (d, J = 7.2 Hz, 1H), 7.97 (t, J = 6.4 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.47 (d, J = 7.6 Hz, 1H), 9.28 (d, J = 9.2 Hz, 1H) ), 9.37 (s, 1H), 9.50 (s, 1H), 12.52 (s, 1H).

実施例１Ａに記載された手順に従い、実施例２Ｂで製造されたＮ−（シクロブチルメチル）−６−ヒドロキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（５０ｍｇ、０.１１ｍｍｏｌ）、及び２−ブロモメチル−ピリジン臭化水素酸塩（７０ｍｇ、０.２８ｍｍｏｌ）を用い、分取型ＨＰＬＣで精製した後、標題の化合物（３１ｍｇ、５２％）を得た。¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.５０−１.７９（ｍ，２Ｈ），１.８１−１.９８（ｍ，２Ｈ），２.０−２.１４（ｍ，２Ｈ），２.４７−２.６２（ｍ，１Ｈ），３.３５（ｔ，Ｊ＝６.９Ｈｚ，２Ｈ），５.４９（ｓ，２Ｈ），６.０５（ｓ，２Ｈ），７.１５（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），７.２１−７.２８（ｍ，１Ｈ），７.３７（ｓ，１Ｈ），７.３９−７.５０（ｍ，２Ｈ），７.５２−７.６３（ｍ，２Ｈ），７.６５−７.７６（ｍ，２Ｈ），７.８２（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.９５−８.０３（ｍ，１Ｈ），８.１３（ｔ，Ｊ＝６.０Ｈｚ，１Ｈ），８.５０−８.６４（ｍ，２Ｈ），９.３５（ｄ，Ｊ＝９.１Ｈｚ，１Ｈ），１２.６１（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５４８.２１。 Example 14
N- (cyclobutylmethyl) -6- (pyridin-2-ylmethoxy) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2- Carboxamide

N- (cyclobutylmethyl) -6-hydroxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) prepared in Example 2B according to the procedure described in Example 1A After purification by preparative HPLC using -1-naphthoyl] amino} pyridine-2-carboxamide (50 mg, 0.11 mmol) and 2-bromomethyl-pyridine hydrobromide (70 mg, 0.28 mmol), The title compound (31 mg, 52%) was obtained. ¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.50-1.79 (m, 2H), 1.81-1.98 (m, 2H), 2.0-2.14 (m, 2H) ), 2.47-2.62 (m, 1H), 3.35 (t, J = 6.9 Hz, 2H), 5.49 (s, 2H), 6.05 (s, 2H), 7. 15 (d, J = 9.1 Hz, 1H), 7.21-7.28 (m, 1H), 7.37 (s, 1H), 7.39-7.50 (m, 2H), 7. 52-7.63 (m, 2H), 7.65-7.76 (m, 2H), 7.82 (d, J = 7.2 Hz, 1H), 7.95-8.03 (m, 1H) ), 8.13 (t, J = 6.0 Hz, 1H), 8.50-8.64 (m, 2H), 9.35 (d, J = 9.1 Hz, 1H), 12.61 (s) , 1H); MS (ESI): (M + H) ⁺ 548.21.

Examples 15 and 16
N- (cyclobutylmethyl) -3-[(4-{[5- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide and N- (cyclobutylmethyl) -3-[(4-{[4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine -2-carboxamide

１−シクロブチルメタンアミン（９１ｍｇ、１.０６ｍｍｏｌ）の無水ＤＭＦ（１ｍＬ）溶液を、実施例１５及び１６：Ｂから得られた３−［（４−｛［５−（メトキシメチル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチル及び３−［（４−｛［４−（メトキシメチル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチル（１５３ ｍｇ）の混合物及び無水ＤＭＦ（２ｍＬ）を含む溶液に加えた。反応混合物を終夜（１８時間）８０℃で撹拌し、次いで室温まで冷却し、ロータリーエバポレーターで濃縮した。残留物をフラッシュクロマトグラフィー（トルエン／ＥｔＯＨ＝１５／１、及びＭＴＢＥ）で精製し、Ｎ−（シクロブチルメチル）−３−［（４−｛［５−（メトキシメチル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボキサミド（４６ｍｇ、粗製のアジドから〜１８％）：
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.７２−１.７７（ｍ，２Ｈ），１.８３−１.９３（ｍ，２Ｈ），２.０３−２.１１（ｍ，２Ｈ），２.４９−２.６１（ｍ，Ｊ＝７.６Ｈｚ，１Ｈ），３.２７（ｓ，３Ｈ），３.３７（ｄ，Ｊ＝６.２Ｈｚ，１Ｈ），３.３９（ｄ，Ｊ＝７.０Ｈｚ，１Ｈ），４.２８（ｓ，２Ｈ），６.１２（ｓ，２Ｈ），７.１０（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.５０（ｄｄ，Ｊ＝４.４，８.７Ｈｚ，１Ｈ），７.５７−７.６３（ｍ，２Ｈ），７.６６（ｓ，１Ｈ），７.７９（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），８.１７−８.２２（ｍ，１Ｈ），８.２６（ｄｄ，Ｊ＝１.４，４.４Ｈｚ，１Ｈ），８.３５−８.４４（ｍ，１Ｈ），８.５３−８.５７（ｍ，１Ｈ），９.３５（ｄｄ，Ｊ＝１.４，８.５Ｈｚ，１Ｈ），１２.８７（ｂｒｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４８５.２；及び、
Ｎ−（シクロブチルメチル）−３−［（４−｛［４−（メトキシメチル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボキサミド（４２ｍｇ、粗製のアジドから約１７％）：
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.７３−１.７７（ｍ，２Ｈ），１.８４−１.９６（ｍ，２Ｈ），２.０４−２.１２（ｍ，２Ｈ），２.５０−２.６２（ｍ，Ｊ＝７.７Ｈｚ，１Ｈ），３.３４（ｓ，３Ｈ），３.３９（ｄ，Ｊ＝６.８Ｈｚ，１Ｈ），３.４１（ｄ，Ｊ＝６.５Ｈｚ，１Ｈ），４.５０（ｓ，２Ｈ），６.００（ｓ，２Ｈ），７.３５（ｓ，１Ｈ），７.４５（ｄ，Ｊ＝７.３Ｈｚ），７.５１（ｄｄ，Ｊ＝４.５，８.６Ｈｚ，１Ｈ），７.５４−７.６１（ｍ，２Ｈ），７.８５（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.９８−８.０２（ｍ，１Ｈ），８.２７（ｄｄ，Ｊ＝１.４，４.４Ｈｚ，１Ｈ），８.４０−８.４５（ｍ，１Ｈ），８.５２−８.５６（ｍ，１Ｈ），９.３７（ｄｄ，Ｊ＝１.３，８.６Ｈｚ，１Ｈ），１２.９１（ｂｒｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４８５.２；
を得た。 Examples 15 and 16: A
N- (cyclobutylmethyl) -3-[(4-{[5- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide and N- (cyclobutylmethyl) -3-[(4-{[4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine -2-carboxamide

A solution of 1-cyclobutylmethanamine (91 mg, 1.06 mmol) in anhydrous DMF (1 mL) was prepared from 3-[(4-{[5- (methoxymethyl) -1H- 1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2-carboxylate and 3-[(4-{[4- (methoxymethyl) -1H-1,2, 3-Triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2-carboxylate (153 mg) was added to a solution containing anhydrous DMF (2 mL). The reaction mixture was stirred overnight (18 hours) at 80 ° C., then cooled to room temperature and concentrated on a rotary evaporator. The residue was purified by flash chromatography (toluene / EtOH = 15/1, and MTBE), and N- (cyclobutylmethyl) -3-[(4-{[5- (methoxymethyl) -1H-1,2, , 3-Triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2-carboxamide (46 mg, ˜18% from crude azide):
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.72-1.77 (m, 2H), 1.83-1.93 (m, 2H), 2.03-2.11 (m, 2H) ), 2.49-2.61 (m, J = 7.6 Hz, 1H), 3.27 (s, 3H), 3.37 (d, J = 6.2 Hz, 1H), 3.39 (d , J = 7.0 Hz, 1H), 4.28 (s, 2H), 6.12 (s, 2H), 7.10 (d, J = 7.3 Hz, 1H), 7.50 (dd, J = 4.4, 8.7 Hz, 1 H), 7.57-7.63 (m, 2 H), 7.66 (s, 1 H), 7.79 (d, J = 7.3 Hz, 1 H), 8 .17-8.22 (m, 1H), 8.26 (dd, J = 1.4, 4.4 Hz, 1H), 8.35-8.44 (m, 1H), 8.53-8. 57 (m, 1H), 9.35 (dd, J = 1.4, 8.5 Hz, 1H), 12.87 ( brs, 1H); MS (ESI): (M + H) ⁺ 485.2; and
N- (cyclobutylmethyl) -3-[(4-{[4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide (42 mg, about 17% from crude azide):
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.73-1.77 (m, 2H), 1.84-1.96 (m, 2H), 2.04-2.12 (m, 2H) ), 2.50-2.62 (m, J = 7.7 Hz, 1H), 3.34 (s, 3H), 3.39 (d, J = 6.8 Hz, 1H), 3.41 (d , J = 6.5 Hz, 1H), 4.50 (s, 2H), 6.00 (s, 2H), 7.35 (s, 1H), 7.45 (d, J = 7.3 Hz), 7.51 (dd, J = 4.5, 8.6 Hz, 1H), 7.54-7.61 (m, 2H), 7.85 (d, J = 7.3 Hz, 1H), 7.98 -8.02 (m, 1H), 8.27 (dd, J = 1.4, 4.4 Hz, 1H), 8.40-8.45 (m, 1H), 8.52-8.56 ( m, 1H), 9.37 (dd, J = 1.3, 8.6 Hz, 1H), 12.91 (brs , 1H); MS (ESI): (M + H) ⁺ 485.2;
Got.

メチルプロパルギルエーテル（０.２３４ｍＬ、２.７７ｍｍｏｌ）を、実施例１５及び１６：Ｃから得た粗製の３−｛［４−（アジドメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル（２００ｍｇ、０.５５３ｍｍｏｌ）及び無水のトルエン（８ｍＬ）を含む懸濁液に加えた。反応容器を密封し、室温で５分間撹拌し、次いで１３０℃で終夜（２０時間）撹拌した。次いで反応混合物を室温に冷却し、ロータリーエバポレーターで濃縮し、そしてフラッシュクロマトグラフィー（ＣＨ₂Ｃｌ₂／ＭｅＯＨ＝３０／１）で精製し、３−［（４−｛［５−（メトキシメチル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチル、及び３−［（４−｛［４−（メトキシメチル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチル（１６４ｍｇ）の混合物を得た。両化合物は、ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺４３２.１を示した。 Examples 15 and 16: B
3-[(4-{[5- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] methyl pyridine-2-carboxylate and 3- [ (4-{[4- (Methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] methyl pyridine-2-carboxylate

Methyl propargyl ether (0.234 mL, 2.77 mmol) was prepared from crude methyl 3-{[4- (azidomethyl) -1-naphthoyl] amino} pyridine-2-carboxylate from Examples 15 and 16: C ( 200 mg, 0.553 mmol) and anhydrous toluene (8 mL). The reaction vessel was sealed and stirred at room temperature for 5 minutes, then stirred at 130 ° C. overnight (20 hours). The reaction mixture is then cooled to room temperature, concentrated on a rotary evaporator and purified by flash chromatography (CH ₂ Cl ₂ / MeOH = 30/1) to give 3-[(4-{[5- (methoxymethyl)- 1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2-carboxylate, and 3-[(4-{[4- (methoxymethyl) -1H-1 , 2,3-Triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2-carboxylate (164 mg). Both compounds exhibited MS (ESI) (M + H) ⁺ 432.1.

抽出可能な水性処理液及び無水のＤＭＦ（１５ｍＬ）により、ブロモ中間体を単離する実施例１Ｄに記載された手順を用い、ナトリウムアジド（２４３ｍｇ、３.７４）を、粗製の３−｛［４−（ブロモメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル（１.２７ｇ、３.１２ｍｍｏｌ）の溶液に加えた。反応混合物を室温で３時間撹拌し、次いで、混合物をトルエン及び水の間で分配した。水相を３回トルエンで抽出し、集めた有機相を乾燥（Ｎａ₂ＳＯ₄）し、ロータリーエバポレーターで濃縮した。残留物をフラッシュクロマトグラフィー（ＣＨ₂Ｃｌ₂／Ｅｔ₂Ｏ＝２０／１）で分離し、粗製の３−｛［４−（アジドメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル （９３２ｍｇ、〜８３％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ ３６２.１。 Examples 15 and 16: C
3-{[4- (Azidomethyl) -1-naphthoyl] amino} methyl 2-pyridine-2-carboxylate

Using the procedure described in Example 1D to isolate the bromo intermediate with extractable aqueous working solution and anhydrous DMF (15 mL), sodium azide (243 mg, 3.74) was added to the crude 3-{[ 4- (Bromomethyl) -1-naphthoyl] amino} pyridine-2-carboxylate (1.27 g, 3.12 mmol) was added to a solution. The reaction mixture was stirred at room temperature for 3 hours and then the mixture was partitioned between toluene and water. The aqueous phase was extracted three times with toluene and the collected organic phases were dried (Na ₂ SO ₄ ) and concentrated on a rotary evaporator. The residue was separated by flash chromatography (CH ₂ Cl ₂ / Et ₂ O = 20/1) and crude methyl 3-{[4- (azidomethyl) -1-naphthoyl] amino} pyridine-2-carboxylate ( 932 mg, ˜83%).
MS (ESI): (M + H) ^<+ > 362.1.

実施例１５及び１６：Ａ〜Ｂと同様の手順を用い、３−ブチン−２−オール（０.２１７ｍＬ、２.７７ｍｍｏｌ）、及び実施例１５及び１６：Ｃから得られた粗製の３−｛［４−（アジドメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル（２００ｍｇ、０.５５３ｍｍｏｌ）より、Ｎ−（シクロブチルメチル）−３−［（４−｛［５−（１−ヒドロキシエチル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボキサミド（５８ｍｇ、粗製アジドから２２％）：
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.５３（ｄ，Ｊ＝７.０Ｈｚ，３Ｈ），１.６７−１.７６（ｍ，２Ｈ），１.８２−１.９４（ｍ，２Ｈ），１.９７（ｄ，Ｊ＝６.８Ｈｚ，１Ｈ），２.０２−２.１２（ｍ，２Ｈ），２.４９−２.６０（ｍ，１Ｈ），３.３７（ｄ，Ｊ＝６.４Ｈｚ，１Ｈ），３.３９（ｄ，Ｊ＝６.６Ｈｚ，１Ｈ），４.７０−４.７６（ｍ，１Ｈ），６.１５（ｄ，Ｊ＝１５.９Ｈｚ，１Ｈ），６.２２（ｄ，Ｊ＝１５.９Ｈｚ，１Ｈ），７.０５（ｄ，Ｊ＝７.４Ｈｚ，１Ｈ），７.４９（ｄｄ，Ｊ＝４.４，８.７Ｈｚ，１Ｈ），７.５８−７.６３（ｍ，３Ｈ），７.７７（ｄ，Ｊ＝７.４Ｈｚ，１Ｈ），８.１７−８.２１（ｍ，１Ｈ），８.２６（ｄｄ，Ｊ＝１.４，４.４Ｈｚ，１Ｈ），８.３８−８.４３（ｍ，１Ｈ），８.５２−８.５６（ｍ，１Ｈ），９.３４（ｄｄ，Ｊ＝１.２，８.７Ｈｚ，１Ｈ），１２.８５（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４８５.２；及び、
Ｎ−（シクロブチルメチル）−３−［（４−｛［４−（１−ヒドロキシエチル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボキサミド（７５ｍｇ、粗製アジドから２８％）：
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.５１（ｄ，Ｊ＝６.４Ｈｚ，３Ｈ），１.６５−１.７６（ｍ，２Ｈ），１.８１−１.９３（ｍ，２Ｈ），２.０１−２.１２（ｍ，２Ｈ），２.２２（ｄ，Ｊ＝４.６Ｈｚ，１Ｈ），２.５０−２.６２（ｍ，１Ｈ），３.３９（ｄ，Ｊ＝６.４Ｈｚ，１Ｈ），３.４１（ｄ，Ｊ＝６.８Ｈｚ，１Ｈ），４.９７−５.０４（ｍ，１Ｈ），５.９９（ｓ，２Ｈ），７.２８（ｓ，１Ｈ），７.４５（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.５１（ｄｄ，Ｊ＝４.４，８.５Ｈｚ，１Ｈ），７.５５−７.６１（ｍ，２Ｈ），７.８５（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），８.００−８.０４（ｍ，１Ｈ），８.２７（ｄｄ，Ｊ＝１.２，４.４Ｈｚ，１Ｈ），８.３９−８.４５（ｍ，１Ｈ），８.５２−８.５６（ｍ，１Ｈ），９.３７（ｄｄ，Ｊ＝１.１，８.５Ｈｚ，１Ｈ），１２.９１（ｂｒｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）＋４８５.２；
を得た。 Examples 17 and 18
N- (cyclobutylmethyl) -3-[(4-{[5- (1-hydroxyethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine- 2-carboxamide and N- (cyclobutylmethyl) -3-[(4-{[4- (1-hydroxyethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl Amino] pyridine-2-carboxamide

Examples 15 and 16: Using a procedure similar to AB, 3-butyn-2-ol (0.217 mL, 2.77 mmol) and Examples 15 and 16: Crude 3- { From methyl [4- (azidomethyl) -1-naphthoyl] amino} pyridine-2-carboxylate (200 mg, 0.553 mmol), N- (cyclobutylmethyl) -3-[(4-{[5- (1- Hydroxyethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2-carboxamide (58 mg, 22% from crude azide):
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.53 (d, J = 7.0 Hz, 3H), 1.67-1.76 (m, 2H), 1.82-1.94 (m , 2H), 1.97 (d, J = 6.8 Hz, 1H), 2.02-2.12 (m, 2H), 2.49-2.60 (m, 1H), 3.37 (d , J = 6.4 Hz, 1H), 3.39 (d, J = 6.6 Hz, 1H), 4.70-4.76 (m, 1H), 6.15 (d, J = 15.9 Hz, 1H), 6.22 (d, J = 15.9 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 7.49 (dd, J = 4.4, 8.7 Hz, 1H) ), 7.58-7.63 (m, 3H), 7.77 (d, J = 7.4 Hz, 1H), 8.17-1.21 (m, 1H), 8.26 (dd, J = 1.4, 4.4 Hz, 1H), 8.38-8.43 (m, 1H), 8.52 −8.56 (m, 1H), 9.34 (dd, J = 1.2, 8.7 Hz, 1H), 12.85 (s, 1H); MS (ESI): (M + H) ⁺ 485.2 ;as well as,
N- (cyclobutylmethyl) -3-[(4-{[4- (1-hydroxyethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine- 2-Carboxamide (75 mg, 28% from crude azide):
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.51 (d, J = 6.4 Hz, 3H), 1.65-1.76 (m, 2H), 1.81-1.93 (m , 2H), 2.01-2.12 (m, 2H), 2.22 (d, J = 4.6 Hz, 1H), 2.50-2.62 (m, 1H), 3.39 (d , J = 6.4 Hz, 1H), 3.41 (d, J = 6.8 Hz, 1H), 4.97-5.04 (m, 1H), 5.99 (s, 2H), 7.28 (S, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.51 (dd, J = 4.4, 8.5 Hz, 1H), 7.55-7.61 (m, 2H), 7.85 (d, J = 7.3 Hz, 1H), 8.00-8.04 (m, 1H), 8.27 (dd, J = 1.2, 4.4 Hz, 1H), 8.39-8.45 (m, 1H), 8.52-8.56 (m, 1H), 9.37 (d d, J = 1.1, 8.5 Hz, 1H), 12.91 (brs, 1H); MS (ESI): (M + H) +485.2;
Got.

実施例１５及び１６：Ａ〜Ｂと同様の手順を用い、実施例１５及び１６：Ｃから得られたプロピオルアミド（１９１ｍｇ、２.７７ｍｍｏｌ）及び粗製の３−｛［４−（アジドメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル（２００ｍｇ、０.５５３ｍｍｏｌ）を用いて、３−［（４−｛［５−（アミノカルボニル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］−Ｎ−（シクロブチルメチル）ピリジン−２−カルボキサミド（３２ｍｇ、粗製アジドから１２％）：
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６６−１.７５（ｍ，２Ｈ），１.８２−１.９３（ｍ，２Ｈ），２.０２−２.１１（ｍ，２Ｈ），２.４９−２.６０（ｍ，１Ｈ），３.３６（ｄ，Ｊ＝６.２Ｈｚ，１Ｈ），３.３８（ｄ，Ｊ＝７.０Ｈｚ，１Ｈ），５.６５（ｂｒｓ，１Ｈ），５.９０（ｂｒｓ，１Ｈ），６.４５（ｓ，２Ｈ），７.２２（ｄ，Ｊ＝７.６Ｈｚ，１Ｈ），７.４９（ｄｄ，Ｊ＝４.５，８.６Ｈｚ，１Ｈ），７.５５−７.６４（ｍ，２Ｈ），７.７６（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.９７（ｓ，１Ｈ），８.２５（ｄｄ，Ｊ＝１.５，４.５Ｈｚ，１Ｈ），８.３１−８.３５（ｍ，１Ｈ），８.３８−８.４１（ｍ，１Ｈ），８.５０−８.５３（ｍ，１Ｈ），９.３５（ｄｄ，Ｊ＝１.４，８.７Ｈｚ，１Ｈ），１２.８１（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４８４.１；及び、
３−［（４−｛［４−（アミノカルボニル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］−Ｎ−（シクロブチルメチル）ピリジン−２−カルボキサミド（３２ｍｇ、粗製アジドから１２％）：
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６８−１.７７（ｍ，２Ｈ），１.８３−１.９４（ｍ，２Ｈ），２.０２−２.１２（ｍ，２Ｈ），２.５０−２.６１（ｍ，１Ｈ），３.３９（ｄ，Ｊ＝６.５，１Ｈ），３.４１（ｄ，Ｊ＝６.８Ｈｚ，１Ｈ），５.４８（ｂｒｓ，１Ｈ），６.０４（ｓ，２Ｈ），６.９７（ｂｒｓ，１Ｈ），７.４８（ｄ，Ｊ＝７.６Ｈｚ，１Ｈ），７.５１（ｄｄ，Ｊ＝４.６，８.７Ｈｚ，１Ｈ），７.５６−７.６２（ｍ，２Ｈ），７.８７（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.９１（ｓ，１Ｈ），７.９５−８.００（ｍ，１Ｈ），８.２７（ｄｄ，Ｊ＝１.４，４.４Ｈｚ，１Ｈ），８.３８−８.４４（ｍ，１Ｈ），８.５５−８.５９（ｍ，１Ｈ），９.３６（ｄｄ，Ｊ＝１.４，８.５Ｈｚ，１Ｈ），１２.９６（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４８４.１；を得た。 Examples 19 and 20
3-[(4-{[5- (aminocarbonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] -N- (cyclobutylmethyl) pyridine-2- Carboxamide, and 3-[(4-{[4- (aminocarbonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] -N- (cyclobutylmethyl) pyridine -2-carboxamide

Examples 15 and 16: Propiolamide obtained from Examples 15 and 16: C (191 mg, 2.77 mmol) and crude 3-{[4- (azidomethyl)- 1-Naphthoyl] amino} pyridine-2-carboxylate methyl (200 mg, 0.553 mmol) was used to give 3-[(4-{[5- (aminocarbonyl) -1H-1,2,3-triazole-1 -Yl] methyl} -1-naphthoyl) amino] -N- (cyclobutylmethyl) pyridine-2-carboxamide (32 mg, 12% from crude azide):
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.66-1.75 (m, 2H), 1.82-1.93 (m, 2H), 2.02-2.11 (m, 2H) ), 2.49-2.60 (m, 1H), 3.36 (d, J = 6.2 Hz, 1H), 3.38 (d, J = 7.0 Hz, 1H), 5.65 (brs) , 1H), 5.90 (brs, 1H), 6.45 (s, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.49 (dd, J = 4.5, 8 .6 Hz, 1 H), 7.55-7.64 (m, 2 H), 7.76 (d, J = 7.3 Hz, 1 H), 7.97 (s, 1 H), 8.25 (dd, J = 1.5, 4.5 Hz, 1H), 8.31-8.35 (m, 1H), 8.38-8.41 (m, 1H), 8.50-8.53 (m, 1H) , 9.35 (dd, J = 1.4, 8.7 Hz, 1H), 12.81 (s, 1 ); MS (ESI) :( M + H) + 484.1; and,
3-[(4-{[4- (Aminocarbonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] -N- (cyclobutylmethyl) pyridine-2- Carboxamide (32 mg, 12% from crude azide):
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.68-1.77 (m, 2H), 1.83-1.94 (m, 2H), 2.02-2.12 (m, 2H) ), 2.50-2.61 (m, 1H), 3.39 (d, J = 6.5, 1H), 3.41 (d, J = 6.8 Hz, 1H), 5.48 (brs) , 1H), 6.04 (s, 2H), 6.97 (brs, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.51 (dd, J = 4.6, 8 .7 Hz, 1H), 7.56-7.62 (m, 2H), 7.87 (d, J = 7.3 Hz, 1H), 7.91 (s, 1H), 7.95-8.00 (M, 1H), 8.27 (dd, J = 1.4, 4.4 Hz, 1H), 8.38-8.44 (m, 1H), 8.55-8.59 (m, 1H) 9.36 (dd, J = 1.4, 8.5 Hz, 1H), 12.96 (s, 1H) ^{MS (ESI) :( M + H} ) + 484.1; was obtained.

Example 21
6- (Aminomethyl) -N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide

実施例２１Ｂから得た６−シアノ−Ｎ−（シクロブチルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキシアミドを、酢酸（２０ｍｌ）中で、１０％Ｐｄ／Ｃ （７０ｍｇ）を触媒として、３時間室温で水素化した。反応混合物をCeliteを通して濾過し、溶媒を減圧下で蒸発させた。残留物を、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／３）及びＣＨ₂Ｃｌ₂／ＭｅＯＨ／ＣＨ₃ＣＯＯＨ（１００／１５／０５）を用いた、シリカゲル上でのカラムクロマトグラフィーで精製し、標題の化合物（４３ｍｇ、５５％）、及びＮ−（シクロブチルメチル）−６−（ヒドロキシメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（２ｍｇ、３％）を得た。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：１．７０−１.９６（ｍ，４Ｈ），２.０−２.１３（ｍ，２Ｈ），２.５５−２.６８（ｍ，１Ｈ），３.３８（ｄ，Ｊ＝７.１８Ｈｚ，２Ｈ），３.９８（ｓ，２Ｈ），６.２１（ｓ，２Ｈ），７.４８（ｄ，Ｊ＝７.４Ｈｚ，１Ｈ），７.５８（ｄ，Ｊ＝８.７Ｈｚ，１Ｈ），７.６０−７.６９（ｍ，２Ｈ），７.７４（ｄ，Ｊ＝１Ｈｚ，１Ｈ），７.８９（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.９６（ｄ，Ｊ＝１Ｈｚ，１Ｈ），８.２０−８.２７（ｍ，１Ｈ），８.４４−８.５０（ｍ，１Ｈ），９.２５（ｄ，Ｊ＝８.６Ｈｚ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４７０.１３。 Example 21A
6- (Aminomethyl) -N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide

6-Cyano-N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-obtained from Example 21B Carboxamide was hydrogenated in acetic acid (20 ml) using 10% Pd / C (70 mg) as a catalyst for 3 hours at room temperature. The reaction mixture was filtered through Celite and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ / MeOH (100/3) and CH ₂ Cl ₂ / MeOH / CH ₃ COOH (100/15/05) as eluents. , The title compound (43 mg, 55%), and N- (cyclobutylmethyl) -6- (hydroxymethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1 -Naphthoyl] amino} pyridine-2-carboxamide (2 mg, 3%) was obtained.
¹ HNMR (300 MHz, CD ₃ OD) δ (ppm): 1.70-1.96 (m, 4H), 2.0-2.13 (m, 2H), 2.55-2.68 (m, 1H), 3.38 (d, J = 7.18 Hz, 2H), 3.98 (s, 2H), 6.21 (s, 2H), 7.48 (d, J = 7.4 Hz, 1H) , 7.58 (d, J = 8.7 Hz, 1H), 7.60-7.69 (m, 2H), 7.74 (d, J = 1 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1 H), 7.96 (d, J = 1 Hz, 1 H), 8.20-8.27 (m, 1 H), 8.44-8.50 (m, 1 H), 9.25 ( d, J = 8.6 Hz, 1H); MS (ESI): (M + H) ⁺ 470.13.

６−シアノ−Ｎ−（シクロブチルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミドを、実施例１Ｄ及び１Ｃに記載の手順（２１Ｃから得られたシクロブタンメチルアミンを用いて）に従い、収率９４％（３６２ｍｇ）で得た。
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.７２−１.８２（ｍ，２Ｈ），１.８９−２.０２（ｍ，２Ｈ），２.１０−２.１９（ｍ，２Ｈ），２.５７−２.６８（ｍ，１Ｈ），３.４７（ｔ，Ｊ＝６.６Ｈｚ，２Ｈ），６.１１（ｓ，２Ｈ），７.４４−７.４７（ｍ，２Ｈ），７.６２−７.６９（ｍ，２Ｈ），７.７４（ｓ，１Ｈ），７.８９−７.９３（ｍ，２Ｈ），８.０７（ｄ，Ｊ＝７.５Ｈｚ，１Ｈ），８.２０−８.２８（ｍ，１Ｈ），８.５８（ｄ，Ｊ＝７.０Ｈｚ，１Ｈ），９.５８（ｄ，Ｊ＝８.９２Ｈｚ，１Ｈ），１３.２５（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４６６.０５。 Example 21B
6-cyano-N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide

6-Cyano-N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide was prepared as Example 1D. And according to the procedure described in 1C (using cyclobutanemethylamine obtained from 21C) in 94% yield (362 mg).
¹ HNMR (500 MHz, CDCl ₃ ) δ (ppm): 1.72-1.82 (m, 2H), 1.89-2.02 (m, 2H), 2.10-2.19 (m, 2H) ), 2.57-2.68 (m, 1H), 3.47 (t, J = 6.6 Hz, 2H), 6.11 (s, 2H), 7.44-7.47 (m, 2H) ), 7.62-7.69 (m, 2H), 7.74 (s, 1H), 7.89-7.93 (m, 2H), 8.07 (d, J = 7.5 Hz, 1H) ), 8.20-8.28 (m, 1H), 8.58 (d, J = 7.0 Hz, 1H), 9.58 (d, J = 8.92 Hz, 1H), 13.25 (s) , 1H); MS (ESI): (M + H) ⁺ 466.05.

実施例２１Ｄで製造した６−クロロ−３−［（４−メチル−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチル（５００ｍｇ、１.４１ｍｍｏｌ）、ＫＣＮ（７５ｍｇ、１.１５ｍｍｏｌ）、Ｐｄ（ＡｃＯ）₂（６３ｍｇ、０.２８ｍｍｏｌ）、１，５−ビス（ジフェニルホスフィノ）ペンタン（２４８ｍｇ、０.５６ｍｍｏｌ）及びＴＭＥＤＡ（３２８ｍｇ、２.８２ｍｍｏｌ）の無水トルエン（２０ ｍｌ）中の混合物を、マイクロウエーブで、１６０℃で４０分間加熱した。反応混合物をジクロロメタンで希釈し、次いで濾過した。溶媒をロータリーエバポレーターで濃縮し、残留物をメタノール中に懸濁させ、還流下で加熱し、次いで室温まで放置して冷却した。結晶を濾過し、メタノールで洗浄し、減圧下で乾燥し、溶離液としてジクロロメタンを用いた、シリカゲル上でのカラムクロマトグラフィーで精製し、標題の化合物（２５０ｍｇ、５１％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺３４６.０５。 Example 21C
Methyl 6-cyano-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate

Methyl 6-chloro-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate (500 mg, 1.41 mmol), KCN (75 mg, 1.15 mmol), Pd (prepared in Example 21D) A mixture of AcO) ₂ (63 mg, 0.28 mmol), 1,5-bis (diphenylphosphino) pentane (248 mg, 0.56 mmol) and TMEDA (328 mg, 2.82 mmol) in anhydrous toluene (20 ml) Heated in a microwave at 160 ° C. for 40 minutes. The reaction mixture was diluted with dichloromethane and then filtered. The solvent was concentrated on a rotary evaporator and the residue was suspended in methanol, heated under reflux and then allowed to cool to room temperature. The crystals were filtered, washed with methanol, dried under reduced pressure and purified by column chromatography on silica gel using dichloromethane as eluent to give the title compound (250 mg, 51%).
MS (ESI): (M + H) ^<+ > 346.05.

Goldbergら [Besly; Goldberg; JCSOA9; J. Chem. Soc.; 2448, 2455]の手順により、６−クロロ−２−メチルピリジン−３−アミンから得られた、３−アミノ−６−クロロピリジン−２−カルボン酸を、実施例１Ｅに記載した手順を用いて、６−クロロ−３−［（４−メチル−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチルに、収率６６％（１１.４２ｇ）で転換した。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ ３５５.１３。 Example 21D
Methyl 6-chloro-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate

3-amino-6-chloropyridine-, obtained from 6-chloro-2-methylpyridin-3-amine by the procedure of Goldberg et al. [Besly; Goldberg; JCSOA9; J. Chem. Soc .; 2448, 2455]. The 2-carboxylic acid was converted to methyl 6-chloro-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate using the procedure described in Example 1E with a yield of 66% .42g).
MS (ESI): (M + H) ^<+ > 355.13.

本化合物を、６−（アミノメチル）−Ｎ−（シクロブチルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミドの合成からの副生成物（２ｍｇ、３％）（実施例２Ａを参照）として単離した。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.５８−１.８１（ｍ，２Ｈ），１.８２−２.０（ｍ，２Ｈ），２.０２−２.２０（ｍ，２Ｈ），２.５１−２.６８（ｍ，１Ｈ），３.４０−３.４８（ｍ，２Ｈ），４.８１（ｓ，２Ｈ），６.０７（ｓ，２Ｈ），７.４１（ｓ，１Ｈ），７.４４（ｄ，Ｊ＝７.４Ｈｚ，１Ｈ），７.５５−７.６５（ｍ，３Ｈ），７.７０（ｓ，１Ｈ），７.８７（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.９８−８.０５（ｍ，１Ｈ），８.２７−８.３７（ｍ，１Ｈ），８.５３−８.６０（ｍ，１Ｈ），９.４２（ｄ，Ｊ＝８.７Ｈｚ，１Ｈ），１２.８９（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺４７１.０９。 Example 21E
N- (cyclobutylmethyl) -6- (hydroxymethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide

This compound was converted to 6- (aminomethyl) -N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2. -Isolated as a by-product from the synthesis of carboxamide (2 mg, 3%) (see Example 2A).
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.58-1.81 (m, 2H), 1.82-2.0 (m, 2H), 2.02-2.20 (m, 2H) ), 2.51-2.68 (m, 1H), 3.40-3.48 (m, 2H), 4.81 (s, 2H), 6.07 (s, 2H), 7.41 ( s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.55-7.65 (m, 3H), 7.70 (s, 1H), 7.87 (d, J = 7.2 Hz, 1H), 7.98-8.05 (m, 1H), 8.27-8.37 (m, 1H), 8.53-8.60 (m, 1H), 9.42 ( d, J = 8.7 Hz, 1H), 12.89 (s, 1H); MS (ESI) (M + H) ⁺ 471.09.

実施例２１Ａから得られた６−（アミノメチル）−Ｎ−（シクロブチルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（４０ｍｇ、０.０８４ｍｍｏｌ）及び無水のジクロロメタン（３ｍｌ）の溶液に、トリエチルアミン（１７ｍｇ、０.１７ｍｍｏｌ）及びメタンスルホニルクロリド（２０ｍｇ、０.１７ｍｍｏｌ）を、窒素雰囲気下、０℃で加えた。反応混合物を室温で３５分間撹拌した。ＣＨ₂Ｃｌ₂を加えた後、反応混合物をＮａＨＣＯ₃（飽和水溶液）で洗浄し、乾燥し、そして減圧下で蒸発させた。残留物を、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／５）を用いた、シリカゲル上でのカラムクロマトグラフィーで精製し、標題の化合物（４５ｍｇ、９７％）を得た。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６９−１.８０（ｍ，２Ｈ），１.８３−１.９８（ｍ，２Ｈ），２.０２−２.１８（ｍ，２Ｈ），２.５１−２.６８（ｍ，１Ｈ），２.９８（ｓ，３Ｈ），３.３８−３.４６（ｍ，２Ｈ），４.４９（ｓ，２Ｈ），５.４５（ｂｒｓ，１Ｈ），６.０６（ｓ，２Ｈ），７.４１（ｓ，１Ｈ），７.４３（ｄ，Ｊ＝７.０Ｈｚ，１Ｈ），７.５２（ｄ，Ｊ＝８.８Ｈｚ，１Ｈ），７.５５−７.６４（ｍ，２Ｈ），７.７０（ｓ，１Ｈ），７.８６（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.９７−８.０４（ｍ，１Ｈ），８.５０−８.６２（ｍ，２Ｈ），９.３９（ｄ，Ｊ＝８.７Ｈｚ，１Ｈ），１２.９４（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５４８。 Example 22
N- (cyclobutylmethyl) -6-{[(methylsulfonyl) amino] methyl} -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-carboxamide

6- (Aminomethyl) -N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} obtained from Example 21A To a solution of pyridine-2-carboxamide (40 mg, 0.084 mmol) and anhydrous dichloromethane (3 ml) was added triethylamine (17 mg, 0.17 mmol) and methanesulfonyl chloride (20 mg, 0.17 mmol) at 0 ° C. under a nitrogen atmosphere. Added in. The reaction mixture was stirred at room temperature for 35 minutes. After adding CH ₂ Cl ₂ , the reaction mixture was washed with NaHCO ₃ (saturated aqueous solution), dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ / MeOH (100/5) as eluent to give the title compound (45 mg, 97%).
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.69-1.80 (m, 2H), 1.83-1.98 (m, 2H), 2.02-2.18 (m, 2H) ), 2.51-2.68 (m, 1H), 2.98 (s, 3H), 3.38-3.46 (m, 2H), 4.49 (s, 2H), 5.45 ( brs, 1H), 6.06 (s, 2H), 7.41 (s, 1H), 7.43 (d, J = 7.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.55-7.64 (m, 2H), 7.70 (s, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.97-8.04 (m, 1H), 8.50-8.62 (m, 2H), 9.39 (d, J = 8.7 Hz, 1H), 12.94 (s, 1H); MS (ESI): (M + H) ⁺ 548 .

実施例２１から得た、６−シアノ−Ｎ−（シクロブチルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（６０ｍｇ、０.１３ｍｍｏｌ）及びＮａＯＨ（２１ｍｇ、水（０.４ｍｌ）に溶解）のメタノール（３ｍｌ）中の混合物を、マイクロウエーブで、８０℃で７分間加熱した。溶液を２ＮのＨＣｌ水溶液でｐＨ４に調節した。溶媒を減圧下で除去した。残留物をジクロロメタンに溶解し、ＮａＨＣＯ₃（飽和の水溶液）で洗浄し、乾燥し、減圧下で除去した。残留物を、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／２）を用いたシリカゲル上でのカラムクロマトグラフィーで精製し、標題の化合物（３１ｍｇ、４８％）を得た。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６３−１.９８（ｍ，４Ｈ），２.０２−２.１８（ｍ，２Ｈ），２.５３−２.６３（ｍ，１Ｈ），３.３８−３.４３（ｍ
，２Ｈ），４.０（ｓ，３Ｈ），６.０６（ｓ，２Ｈ），７.３８−７.４２（ｍ，２Ｈ），７.５７−７.６３（ｍ，２Ｈ），７.７２（ｓ，１Ｈ），７.９（ｄ，１Ｈ），７.９６−８.０６（ｍ，１Ｈ），８.３（ｄ，１Ｈ），８.４５−８.５８（ｍ，２Ｈ），９.４５（ｄ，１Ｈ），１３.１８（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４９９。 Example 23
6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} methyl methyl pyridine-2-carboxylate

6-Cyano-N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2 obtained from Example 21 A mixture of carboxamide (60 mg, 0.13 mmol) and NaOH (21 mg, dissolved in water (0.4 ml)) in methanol (3 ml) was heated in a microwave at 80 ° C. for 7 minutes. The solution was adjusted to pH 4 with 2N aqueous HCl. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, washed with NaHCO ₃ (saturated aqueous solution), dried and removed under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ / MeOH (100/2) as eluent to give the title compound (31 mg, 48%).
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.63-1.98 (m, 4H), 2.02-2.18 (m, 2H), 2.53-2.63 (m, 1H ), 3.38-3.43 (m
, 2H), 4.0 (s, 3H), 6.06 (s, 2H), 7.38-7.42 (m, 2H), 7.57-7.63 (m, 2H), 7. 72 (s, 1H), 7.9 (d, 1H), 7.96-8.06 (m, 1H), 8.3 (d, 1H), 8.45-8.58 (m, 2H) , 9.45 (d, 1H), 13.18 (s, 1H); MS (ESI): (M + H) ⁺ 499.

実施例２１Ｂから得た６−シアノ−Ｎ−（シクロブチルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（４５ｍｇ、０.０９７ｍｍｏｌ）及びＮａＯＨ（３７ｍｇ、水（０.８ｍｌ）に溶解）及びエタノール（２.７ｍｌ）の混合物を、マイクロウエーブで、８０℃で５分間加熱した。溶液を２ＮのＨＣｌ水溶液でｐＨ４に調節した。溶媒を減圧下で除去した。エタノール（１ｍｌ）及び水（１.５ｍｌ）を加えた。生成した沈殿物を集め、水、エタノール及びエーテルで洗浄し、次いで減圧下で乾燥し、標題の化合物（３３ｍｇ、７０％）を得た。
¹ＨＮＭＲ（５００ＭＨｚ，ＤＭＳＯ−ｄ₆）δ（ｐｐｍ）：１.６４−１.７３（ｍ，２Ｈ），１.７４−１.８４（ｍ，２Ｈ），１.９１−２.０（ｍ，２Ｈ），２.４８−２.５８（ｍ，１Ｈ），３.３２−３.４２（ｍ，２Ｈ），６.２２（ｓ，２Ｈ），７.３９（ｄ，Ｊ＝７.５Ｈｚ，１Ｈ），７.６４−７.７４（ｍ，３Ｈ），７.７８（ｓ，１Ｈ），７.９１（ｄ，Ｊ＝７.５Ｈｚ，１Ｈ），８.２５（ｓ，１Ｈ），８.２７−８.３４（ｍ，２Ｈ），８.４２（ｄ，Ｊ＝８.４Ｈｚ，１Ｈ），８.８０（ｓ，１Ｈ），９.３４（ｄ，Ｊ＝８.４Ｈｚ，１Ｈ），９.７２（ｔ，Ｊ＝６.１Ｈｚ，１Ｈ），１３.２３（ｓ，１Ｈ）.ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４８４.０８。 Example 24
N ² - (cyclobutylmethyl) -3 - {[4- (1H -1,2,3- triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2,6-dicarboxamide

6-Cyano-N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-obtained from Example 21B A mixture of carboxamide (45 mg, 0.097 mmol) and NaOH (37 mg, dissolved in water (0.8 ml)) and ethanol (2.7 ml) was heated in a microwave at 80 ° C. for 5 minutes. The solution was adjusted to pH 4 with 2N aqueous HCl. The solvent was removed under reduced pressure. Ethanol (1 ml) and water (1.5 ml) were added. The resulting precipitate was collected, washed with water, ethanol and ether and then dried under reduced pressure to give the title compound (33 mg, 70%).
¹ H NMR (500 MHz, DMSO-d ₆ ) δ (ppm): 1.64-1.73 (m, 2H), 1.74-1.84 (m, 2H), 1.91-2. , 2H), 2.48-2.58 (m, 1H), 3.32-3.42 (m, 2H), 6.22 (s, 2H), 7.39 (d, J = 7.5 Hz , 1H), 7.64-7.74 (m, 3H), 7.78 (s, 1H), 7.91 (d, J = 7.5 Hz, 1H), 8.25 (s, 1H), 8.27-8.34 (m, 2H), 8.42 (d, J = 8.4Hz, 1H), 8.80 (s, 1H), 9.34 (d, J = 8.4Hz, 1H) ), 9.72 (t, J = 6.1 Hz, 1H), 13.23 (s, 1H). MS (ESI): (M + H) ⁺ 484.08.

Example 25
N- (cyclobutylmethyl) -6-methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2-carboxamide

実施例２５Ｂで製造した６−メトキシ−５−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピラジン−２−カルボン酸 （０.０３４ｇ、０.０６ｍｍｏｌ、１当量）及び１滴のＮ，Ｎ−ジメチルホルミアミドのクロロホルム（６ｍＬ）中の混合物に、オキサリルクロリド（０.０９３ｇ、０.７３ｍｍｏｌ、１１.１当量（ｅｑ））のクロロホルム（２ｍＬ）溶液を加えた。カルボン酸が、完全にカルボニルクロリドに変化したことをＬＣ／ＭＳが示すまで、混合物を９０℃で３時間加熱した。溶媒を減圧下で除去した。残留物に、Ｎ，Ｎ−ジイソプロピルエチルアミン（０.０７７ｇ、０.５９ｍｍｏｌ、９.１当量）及びシクロブチルメチルアミン（０.０３１ｇ、０.３６ｍｍｏｌ、５.５当量）の無水アセトニトリル溶液（１０ｍｌ）を加えた。混合物を室温で５時間撹拌した。溶媒を除去した後、残留物をジメチルスルホキシド（５ｍＬ）に溶解した。得られた溶液を逆相分取型ＨＰＬＣで精製した。凍結乾燥して標題の化合物（０.００７ｇ、１８％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２２−１.４２（ｍ，２Ｈ），１.６１（ｄ，Ｊ＝１２.８Ｈｚ，２Ｈ），１.６７−１.８０（ｍ，３Ｈ），１.８３−１.９８（ｍ，４Ｈ），２.００−２.１４（ｍ，２Ｈ），２.５５（ｍ，１Ｈ），３.２７−３.４３（ｍ，４Ｈ），３.９７（ｍ，２Ｈ），３.９８（ｓ，３Ｈ），５.５９（ｂｒｓ，１Ｈ），６.０７（ｓ，２Ｈ），７.３４−７.４９（ｍ，３Ｈ），７.５６（ｍ，２Ｈ），７.６８（ｓ，１Ｈ），７.８１（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.９７（ｍ，１Ｈ），８.５５（ｍ，１Ｈ），１２.２９（ｓ，１Ｈ）。 Example 25A
N- (cyclobutylmethyl) -6-methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2-carboxamide

6-Methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1 prepared in Example 25B -Naphthoyl] amino} pyrazine-2-carboxylic acid (0.034 g, 0.06 mmol, 1 eq) and a drop of N, N-dimethylformamide in chloroform (6 mL) was added to oxalyl chloride (0.0 A solution of 093 g, 0.73 mmol, 11.1 eq (eq)) in chloroform (2 mL) was added. The mixture was heated at 90 ° C. for 3 hours until LC / MS showed that the carboxylic acid was completely converted to carbonyl chloride. The solvent was removed under reduced pressure. To the residue was added N, N-diisopropylethylamine (0.077 g, 0.59 mmol, 9.1 eq) and cyclobutylmethylamine (0.031 g, 0.36 mmol, 5.5 eq) in anhydrous acetonitrile (10 ml). Was added. The mixture was stirred at room temperature for 5 hours. After removing the solvent, the residue was dissolved in dimethyl sulfoxide (5 mL). The resulting solution was purified by reverse phase preparative HPLC. Lyophilization gave the title compound (0.007 g, 18%).
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.22-1.42 (m, 2H), 1.61 (d, J = 12.8 Hz, 2H), 1.67-1.80 (m 3H), 1.83-1.98 (m, 4H), 2.00-2.14 (m, 2H), 2.55 (m, 1H), 3.27-3.43 (m, 4H) ), 3.97 (m, 2H), 3.98 (s, 3H), 5.59 (brs, 1H), 6.07 (s, 2H), 7.34-7.49 (m, 3H) , 7.56 (m, 2H), 7.68 (s, 1H), 7.81 (d, J = 7.3 Hz, 1H), 7.97 (m, 1H), 8.55 (m, 1H) ), 12.29 (s, 1H).

実施例２５Ｃで製造した６−メトキシ−５−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）アミノ］−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピラジン−２−カルボン酸メチル（０.０３５ｇ、０.０７ｍｍｏｌ、１当量）のメタノール（３ｍＬ）中の混合物に、水酸化リチウム（０.０１３ｍｇ、０.５４ｍｍｏｌ、８.２当量）の水溶液（２ｍＬ）を加えた。得られた混合物を、
終夜室温で撹拌した。加水分解が完了したことをＬＣ／ＭＳが示した時、混合物を酢酸（０.１２９ｇ、２.２ｍｍｏｌ、３０当量）で中和した。溶媒を減圧下で除去した。得られた固体を、更なる精製を行わず、直接次の工程で用いた。 Example 25B
6-methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine -2-carboxylic acid

6-Methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1 prepared in Example 25C -Naphthoyl] amino} pyrazine-2-carboxylate (0.035 g, 0.07 mmol, 1 eq) in methanol (3 mL) was added to lithium hydroxide (0.013 mg, 0.54 mmol, 8.2 eq). ) In water (2 mL) was added. The resulting mixture is
Stir overnight at room temperature. When LC / MS showed that the hydrolysis was complete, the mixture was neutralized with acetic acid (0.129 g, 2.2 mmol, 30 eq). The solvent was removed under reduced pressure. The resulting solid was used directly in the next step without further purification.

実施例２５Ｄで製造した５−クロロ−６−メトキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピラジン−２−カルボン酸メチル（０.０６０ｇ、０.１３ｍｍｏｌ、１当量）及び（テトラヒドロ−ピラン−４−イル）−メチルアミン（０.０６４ｇ、０.５６ｍｍｏｌ、４.２当量）の無水ジメチルホルミアミド（５ｍＬ）溶液を、出発物質が消費されたことをＬＣ／ＭＳが示すまで、１２０℃で３時間加熱した。反応混合物を室温に冷却し、そして溶液を逆相分取型ＨＰＬＣで精製した。凍結乾燥して、標題の化合物（０.０３５ｇ、５０％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ₆）δ（ｐｐｍ）：０.９０（ｄｔ，Ｊ＝９.５，１１.２Ｈｚ，２Ｈ），１.２７（ｄ，Ｊ＝１２.７Ｈｚ，２Ｈ），１.６４（ｍ，１Ｈ），２.７５（ｂｒｓ，２Ｈ），３.１２（ｔ，Ｊ＝１１.０Ｈｚ，２Ｈ），３.６９−３.７９（ｍ，２Ｈ），６.１７（ｓ，２Ｈ），７.３７（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.５６−７.７０（ｍ，４Ｈ），７.７６（ｄ，Ｊ＝０.６Ｈｚ，１Ｈ），８.２０（ｄ，Ｊ＝０.６Ｈｚ，１Ｈ），８.２４（ｄ，Ｊ＝７.７Ｈｚ，１Ｈ），８.２９（ｄ，Ｊ＝７.７Ｈｚ，１Ｈ），１０.８４（ｓ，１Ｈ）。 Example 25C
6-methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine 2-Carboxylic acid methyl

Methyl 5-chloro-6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2-carboxylate prepared in Example 25D ( 0.060 g, 0.13 mmol, 1 eq) and (tetrahydro-pyran-4-yl) -methylamine (0.064 g, 0.56 mmol, 4.2 eq) in anhydrous dimethylformamide (5 mL) were added. Heated at 120 ° C. for 3 hours until LC / MS indicated that the starting material was consumed. The reaction mixture was cooled to room temperature and the solution was purified by reverse phase preparative HPLC. Lyophilization gave the title compound (0.035 g, 50%).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 0.90 (dt, J = 9.5, 11.2 Hz, 2H), 1.27 (d, J = 12.7 Hz, 2H), 1 .64 (m, 1H), 2.75 (brs, 2H), 3.12 (t, J = 11.0 Hz, 2H), 3.69-3.79 (m, 2H), 6.17 (s , 2H), 7.37 (d, J = 7.3 Hz, 1H), 7.56-7.70 (m, 4H), 7.76 (d, J = 0.6 Hz, 1H), 8.20 (D, J = 0.6 Hz, 1H), 8.24 (d, J = 7.7 Hz, 1H), 8.29 (d, J = 7.7 Hz, 1H), 10.84 (s, 1H) .

実施例２５Ｅで製造した５−クロロ−６−メトキシ−３−［（４−メチル−１−ナフトイル）アミノ］ピラジン−２−カルボン酸メチル（０.２５８ｇ、０.６７ｍｍｏｌ、１当量）、Ｎ−ブロモスクシンイミド（０.１２３ｇ、０.６９ｍｍｏｌ、１.０当量）及び過酸化ベンゾイル（０.０１８ｇ、０.０７ｍｍｏｌ、０.１１当量）の四塩化炭素（１００ｍｌ）中の混合物を、ブロモ化が完了したことをＬＣ／ＭＳが示すまで、１時間還流した。反応混合物を５０℃に冷却し、１，２，３−トリアゾール（０.２４５ｇ、３.５５ｍｍｏｌ、５.３当量）を加えた。得られた混合物を、反応が完了したことをＬＣ／ＭＳが示すまで、８０℃で２時間撹拌した。溶媒を減圧下で除去した。残留物をジメチルスルホキシド（１０ｍＬ）に溶解した。ジメチルスルホキシド溶液を逆相分取型ＨＰＬＣで精製した。凍結乾燥して、標題の化合物（０.０６２ｇ、２１％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ₆）δ（ｐｐｍ）：３.８０（ｓ，３Ｈ），４.０１（ｓ，３Ｈ），５.７２（ｓ，１Ｈ），６.１６（ｓ，２Ｈ），７.３７（ｄ，Ｊ＝７.２Ｈｚ，１Ｈ），７.６３（ｍ，２Ｈ），７.７１（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.７３（ｓ，１Ｈ），８.１８（ｓ，１Ｈ），８.２６（ｍ，２Ｈ），１１.４１（ｂｒｓ，１Ｈ）。 Example 25D
5-Chloro-6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} methyl pyrazine-2-carboxylate

Methyl 5-chloro-6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyrazine-2-carboxylate prepared in Example 25E (0.258 g, 0.67 mmol, 1 eq), N- Bromination was completed with a mixture of bromosuccinimide (0.123 g, 0.69 mmol, 1.0 equiv) and benzoyl peroxide (0.018 g, 0.07 mmol, 0.11 equiv) in carbon tetrachloride (100 ml). Refluxed for 1 hour until LC / MS indicated. The reaction mixture was cooled to 50 ° C. and 1,2,3-triazole (0.245 g, 3.55 mmol, 5.3 eq) was added. The resulting mixture was stirred at 80 ° C. for 2 hours until LC / MS indicated that the reaction was complete. The solvent was removed under reduced pressure. The residue was dissolved in dimethyl sulfoxide (10 mL). The dimethyl sulfoxide solution was purified by reverse phase preparative HPLC. Lyophilization gave the title compound (0.062 g, 21%).
¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.80 (s, 3H), 4.01 (s, 3H), 5.72 (s, 1H), 6.16 (s, 2H) 7.37 (d, J = 7.2 Hz, 1H), 7.63 (m, 2H), 7.71 (d, J = 7.3 Hz, 1H), 7.73 (s, 1H), 8 .18 (s, 1H), 8.26 (m, 2H), 11.41 (brs, 1H).

実施例２５Ｆで製造した６−メトキシ−３−［（４−メチル−１−ナフトイル）アミノ］ピラジン−２−カルボン酸メチル（０.３７５ｇ、１.０７ｍｍｏｌ、ｌ当量）、Ｎ−クロロスクシンイミド（０.２４８ｇ、１.８６ｍｍｏｌ １.７当量）の無水アセトニトリル（１８ｍＬ）中の混合物を、マイクロウエーブで、１２０℃で１０分間加熱した。ＬＣ／ＭＳは、出発物質のメチルエステルが消費されたことを示した。溶液を逆相分取型ＨＰＬＣで精製した。凍結乾燥して、標題の化合物（０.３１８ｇ、７７％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ₆）δ（ｐｐｍ）：３.８４（ｓ，３Ｈ），３.９７（ｓ，３Ｈ），６.２０（ｓ，２Ｈ），７.４２（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.６７（ｍ，２Ｈ），７.７４（ｄ，Ｊ＝７.３Ｈｚ，１Ｈ），７.７７（ｄ，Ｊ＝０.８Ｈｚ，１Ｈ），８.２１（ｄ，Ｊ＝０.８Ｈｚ，１Ｈ），８.３０（ｍ，２Ｈ），８.４３（ｓ，１Ｈ），１１.２９（ｂｒｓ，１Ｈ）。 Example 25E
Methyl 5-chloro-6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyrazine-2-carboxylate

Methyl 6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyrazine-2-carboxylate (0.375 g, 1.07 mmol, 1 eq) prepared in Example 25F, N-chlorosuccinimide (0 A mixture of .248 g, 1.86 mmol, 1.7 eq) in anhydrous acetonitrile (18 mL) was heated in a microwave at 120 ° C. for 10 minutes. LC / MS showed that the starting methyl ester was consumed. The solution was purified by reverse phase preparative HPLC. Lyophilization gave the title compound (0.318 g, 77%).
¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.84 (s, 3H), 3.97 (s, 3H), 6.20 (s, 2H), 7.42 (d, J = 7.3 Hz, 1 H), 7.67 (m, 2 H), 7.74 (d, J = 7.3 Hz, 1 H), 7.77 (d, J = 0.8 Hz, 1 H), 8.21 ( d, J = 0.8 Hz, 1H), 8.30 (m, 2H), 8.43 (s, 1H), 11.29 (brs, 1H).

実施例２５Ｇで製造した３−アミノ−６−メトキシピラジン−２−カルボン酸メチル（１.５６０ｇ、８.５２ｍｍｏｌ、１当量）、４−メチル−ナフタレン−１−カルボニルクロリド（１.８３０ｇ、８.９４ｍｍｏｌ、１.０５当量）、４−ジメチルアミノピリジン（０.１１７ｇ、０.９５ｍｍｏｌ、０.１１当量）及び無水ピリジン（２.７１６ｇ、３４.３４ｍｍｏｌ、４.０３当量）の無水クロロホルム（１５０ｍＬ）溶液を、ＬＣ／ＭＳに従って出発物質が無くなっていることが判明するまで、室温で撹拌した。溶媒を減圧下で除去した。残留物を、酢酸エチル／ヘキサンで溶出するシリカゲル上でのフラッシュクロマトグラフィーで精製し、所望の生成物（１.８３２ｇ、６１％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ₆）δ（ｐｐｍ）：２.７２（ｓ，３Ｈ），３.８３（ｓ，３Ｈ），３.９８（ｓ，３Ｈ），７.４８（ｄ，Ｊ＝７.４Ｈｚ，１Ｈ），７.６２（ｍ，２Ｈ），７.６８（ｄ，Ｊ＝７.４Ｈｚ，１Ｈ），８.１２（ｍ，１Ｈ），８.３１（ｍ，１Ｈ），８.４３（ｓ，１Ｈ），１１.１９（ｂｒｓ，１Ｈ）。 Example 25F
Methyl 6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyrazine-2-carboxylate

Methyl 3-amino-6-methoxypyrazine-2-carboxylate (1.560 g, 8.52 mmol, 1 equivalent) prepared in Example 25G, 4-methyl-naphthalene-1-carbonyl chloride (1.830 g, 8. 94 mmol, 1.05 eq), 4-dimethylaminopyridine (0.117 g, 0.95 mmol, 0.11 eq) and anhydrous pyridine (2.716 g, 34.34 mmol, 4.03 eq) in anhydrous chloroform (150 mL) The solution was stirred at room temperature until found to be free of starting material according to LC / MS. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate / hexanes to give the desired product (1.832 g, 61%).
¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.72 (s, 3H), 3.83 (s, 3H), 3.98 (s, 3H), 7.48 (d, J = 7.4 Hz, 1 H), 7.62 (m, 2 H), 7.68 (d, J = 7.4 Hz, 1 H), 8.12 (m, 1 H), 8.31 (m, 1 H), 8 .43 (s, 1H), 11.19 (brs, 1H).

実施例２５Ｈで製造した３−アミノ−６−メトキシピラジン−２−カルボン酸（１.８２１ｇ、１０.７７ｍｍｏｌ、１当量）の無水１，４−ジオキサン（４０ｍＬ）溶液に、トリエチルアミン５ｍＬ（３.６３５ｇ、３５.９２ｍｍｏｌ、３.３４当量）を加えた。混合物に超音波をあてて、カルボン酸を完全にトリエチルアンモニウム塩に転換させた。反応混合物を氷水浴内で冷却し、クロロギ酸エチル（１.７２５ｇ、１５.９０ｍｍｏｌ、１.４８当量）を加えた。反応混合物を０℃で１０分間撹拌し、次いで室温まで温めた。反応混合物を、ＬＣ／ＭＳが出発物質が残留していないことを示すまで、継続して、更に２０分間撹拌した。混合物に無水メタノール（２０ｍＬ）を加え、そして得られた混合物を１時間撹拌した。溶媒を減圧下で除去した。残留物をジクロロメタン／水で２回抽出した。有機層を集め、水ですすぎ、無水硫酸ナトリウムで乾燥し、減圧下で濃縮し、固体を得た。固体を温メタノール中に溶解し、そして活性炭を加えて生成物を脱色した。濾過した後、若干黄色味を帯びた結晶性固体（１.５８４ｇ、８０％）を冷メタノール溶液から得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ₆）δ（ｐｐｍ）：３.７７（ｓ，３Ｈ），３.７９（ｓ，３Ｈ），６.９２（ｓ，２Ｈ），８.０９（ｓ，１Ｈ）。 Example 25G
Methyl 3-amino-6-methoxypyrazine-2-carboxylate

To a solution of 3-amino-6-methoxypyrazine-2-carboxylic acid prepared in Example 25H (1.821 g, 10.77 mmol, 1 eq) in anhydrous 1,4-dioxane (40 mL) was added 5 mL (3.635 g) of triethylamine. 35.92 mmol, 3.34 equiv.). The mixture was sonicated to completely convert the carboxylic acid to the triethylammonium salt. The reaction mixture was cooled in an ice-water bath and ethyl chloroformate (1.725 g, 15.90 mmol, 1.48 eq) was added. The reaction mixture was stirred at 0 ° C. for 10 minutes and then allowed to warm to room temperature. The reaction mixture was continued to stir for an additional 20 minutes until LC / MS showed no starting material remained. To the mixture was added anhydrous methanol (20 mL) and the resulting mixture was stirred for 1 hour. The solvent was removed under reduced pressure. The residue was extracted twice with dichloromethane / water. The organic layer was collected, rinsed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a solid. The solid was dissolved in warm methanol and activated carbon was added to decolorize the product. After filtration, a slightly yellowish crystalline solid (1.584 g, 80%) was obtained from the cold methanol solution.
¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.77 (s, 3H), 3.79 (s, 3H), 6.92 (s, 2H), 8.09 (s, 1H) .

実施例２５Ｉで製造した６−ブロモ−３−（３−クロロフェニル）プテリジン−２，４（１Ｈ，３Ｈ）−ジオン（６.７５０ｇ、１９.１０ｍｍｏｌ、１当量）を、ナトリウムメトキシド（３.０９４ｇ、５７.２７ｍｍｏｌ、３当量）の３０％無水メタノール（８４ｍＬ）溶液に混合した。混合物を１３０℃で２０時間加熱した。ＬＣ／ＭＳは出発物質が消費されたことを示した。溶媒を減圧下で除去した。残留物に、水酸化ナトリウムの水溶液（１.１４５ｇ、２８.６４ｍｍｏｌ、１.５当量の水溶液（１５０ｍｌ））を加えた。混合物を反応が完了するまで２０時間還流した。次いで、反応混合物を放置して室温に戻し、微量の不溶性固体を濾別した。濾液を活性炭で脱色し、そして半分の体積になるまで蒸発させた。得られた溶液を、ｐＨ２〜３になるまで４Ｎの塩酸水溶液で中和した。室温で１時間放置した後、生成した固体を濾過し、冷水で２回濯ぎ、そして減圧下で乾燥し、固体（２.６５ｇ、８２％）を得た。これは、更なる精製をせずにメチル化用として使用した。
¹ＨＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ₆）δ（ｐｐｍ）：３.８３（ｓ，３Ｈ），８.１０（ｓ，１Ｈ）。 Example 25H
3-Amino-6-methoxypyrazine-2-carboxylic acid

6-Bromo-3- (3-chlorophenyl) pteridine-2,4 (1H, 3H) -dione prepared in Example 25I (6.750 g, 19.10 mmol, 1 eq) was added to sodium methoxide (3.094 g). , 57.27 mmol, 3 eq) in 30% anhydrous methanol (84 mL). The mixture was heated at 130 ° C. for 20 hours. LC / MS indicated that the starting material was consumed. The solvent was removed under reduced pressure. To the residue was added an aqueous solution of sodium hydroxide (1.145 g, 28.64 mmol, 1.5 eq. Aqueous solution (150 ml)). The mixture was refluxed for 20 hours until the reaction was complete. The reaction mixture was then allowed to return to room temperature and a trace amount of insoluble solid was filtered off. The filtrate was decolorized with activated carbon and evaporated to half volume. The resulting solution was neutralized with 4N aqueous hydrochloric acid until pH 2-3. After standing at room temperature for 1 hour, the resulting solid was filtered, rinsed twice with cold water, and dried under reduced pressure to give a solid (2.65 g, 82%). This was used for methylation without further purification.
¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.83 (s, 3H), 8.10 (s, 1H).

実施例２５Ｊで製造した３−アミノ−６−ブロモピラジン−２−カルボン酸メチル（１１.４７６ｇ、４９.４５ｍｍｏｌ、１当量）の無水ピリジン溶液（６０ｍＬ）に、３−クロロフェニルイソシアナート（８.８２ｇ、５７.４３ｍｍｏｌ、１.２当量）を加えた。混合物を１５０℃で４時間還流した。溶媒を減圧下で除去した。残留物にブラインを加えた。混合物をジクロロメタンで３回に分けて抽出した。有機相を集め、飽和の炭酸水素ナトリウム水溶液で濯ぎ、そして減圧下で蒸発させた。得られた残留物を温酢酸エチルに溶解した。終夜放置した後、粗製の生成物を固体として得た。追加の生成物を母液から抽出した。このようにして、所望の生成物（８.０１２ｇ）を得た。３−アミノ−２−ピラジンカルボン酸メチルの収率は、２工程で５７％であった。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：７.１９（ｄｔ，Ｊ＝２.０，４.５Ｈｚ，１Ｈ），７.３１（ｓ，１Ｈ），７.４８（ｄ，Ｊ＝４.９Ｈｚ，１Ｈ），８.６９（ｓ，１Ｈ）。 Example 25I
6-Bromo-3- (3-chlorophenyl) pteridine-2,4 (1H, 3H) -dione

To a solution of methyl 3-amino-6-bromopyrazine-2-carboxylate (11.476 g, 49.45 mmol, 1 equivalent) prepared in Example 25J in anhydrous pyridine (60 mL) was added 3-chlorophenyl isocyanate (8.82 g). 57.43 mmol, 1.2 eq.). The mixture was refluxed at 150 ° C. for 4 hours. The solvent was removed under reduced pressure. Brine was added to the residue. The mixture was extracted with dichloromethane in three portions. The organic phase was collected, rinsed with saturated aqueous sodium bicarbonate solution and evaporated under reduced pressure. The resulting residue was dissolved in warm ethyl acetate. After standing overnight, the crude product was obtained as a solid. Additional product was extracted from the mother liquor. There was thus obtained the desired product (8.012 g). The yield of methyl 3-amino-2-pyrazinecarboxylate was 57% over two steps.
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 7.19 (dt, J = 2.0, 4.5 Hz, 1H), 7.31 (s, 1H), 7.48 (d, J = 4 .9 Hz, 1 H), 8.69 (s, 1 H).

３−アミノピラジン−２−カルボン酸メチル（６.３０ｇ、４１.１４ｍｍｏｌ、１当量）及びＮ−ブロモスクシンイミド（７.３２２ｇ、４１.１４ｍｍｏｌ、１当量）のアセトニトリル（１００ｍＬ）中の混合物を、ＬＣ／ＭＳにより出発物質が残留していないことを確認するまで２時間還流した。溶媒を減圧下で除去した。残留物にイソプロパノールを加えた。濾過した後、粗製の生成物を固体として集めた。追加の生成物は、母液から集めることが出来た。このようにして、粗製の生成物（１２.１３６ｇ、１２７％）を得た。粗製の生成物は、更に精製せずに次の工程で用いた。
¹ＨＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ₆）δ（ｐｐｍ）：３.８５（ｓ，３Ｈ），７.５５（ｂｒｓ，２Ｈ），８.４２（ｓ，１Ｈ）。 Example 25J
Methyl 3-amino-6-bromopyrazine-2-carboxylate

A mixture of methyl 3-aminopyrazine-2-carboxylate (6.30 g, 41.14 mmol, 1 eq) and N-bromosuccinimide (7.322 g, 41.14 mmol, 1 eq) in acetonitrile (100 mL) was added to the LC. / MS was refluxed for 2 hours until no starting material was confirmed. The solvent was removed under reduced pressure. Isopropanol was added to the residue. After filtration, the crude product was collected as a solid. Additional product could be collected from the mother liquor. In this way a crude product (12.136 g, 127%) was obtained. The crude product was used in the next step without further purification.
¹ HNMR (400 MHz, DMSO-d ₆ ) δ (ppm): 3.85 (s, 3H), 7.55 (brs, 2H), 8.42 (s, 1H).

実施例４に記載された手順に従い、実施例３で製造した［（６−｛［（シクロブチルメチル）アミノ］カルボニル｝−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−イル）オキシ］酢酸（４４ｍｇ、０.０８６ｍｍｏｌ）、及びモルホリン（２０ｍｇ、０.２３ｍｍｏｌ）を用いて処理した後、標題の化合物（４７ｍｇ、９４％）を得た。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.７０−２.０（ｍ，４Ｈ），２.０２−２.２０（ｍ，２Ｈ），２.５６−２.７２（ｍ，１Ｈ），３.３７−３−４４（ｍ，２Ｈ），３.５１−３.６７（ｍ，８Ｈ），３.８４（ｓ，２Ｈ），６.５０（ｓ，２Ｈ），７.０６（ｄ，１Ｈ），７.３９（ｓ，１Ｈ），７.４２（ｄ，１Ｈ），７.５２−７.６４（ｍ，２Ｈ），７.６８（ｓ，１Ｈ），７.８４（ｄ，１Ｈ），７.９５−８.０４（ｍ，１Ｈ），８.４５（”ｔ”，１Ｈ），８.５０−８.５９（ｍ，１Ｈ），９.３９（ｄ，１Ｈ），１２.７１（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺５８４.０９。 Example 26
6- (2-morpholin-4-yl-2-oxoethoxy) -3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2- Carboxylic acid cyclobutylmethyl-amide

[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole-1) prepared in Example 3 according to the procedure described in Example 4 After treatment with -ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy] acetic acid (44 mg, 0.086 mmol) and morpholine (20 mg, 0.23 mmol), the title compound (47 mg, 94 %).
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.70-2.0 (m, 4H), 2.02-2.20 (m, 2H), 2.56-2.72 (m, 1H ), 3.37-3-44 (m, 2H), 3.51-3.67 (m, 8H), 3.84 (s, 2H), 6.50 (s, 2H), 7.06 ( d, 1H), 7.39 (s, 1H), 7.42 (d, 1H), 7.52-7.64 (m, 2H), 7.68 (s, 1H), 7.84 (d , 1H), 7.95-8.04 (m, 1H), 8.45 ("t", 1H), 8.50-8.59 (m, 1H), 9.39 (d, 1H), 12.71 (s, 1 H); MS (ESI) (M + H) ⁺ 584.09.

実施例４に記載された手順に従い、実施例３で製造した［（６−｛［（シクロブチルメチル）アミノ］カルボニル｝−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−イル）オキシ］酢酸（４０ｍｇ、０.０７８ｍｍｏｌ）、及びベンジルアミン（２５ｍｇ、０.２３ｍｍｏｌ）を用い、シリカゲル上で、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／２.２５）を用いたカラムクロマトグラフィーで精製した後、標題の化合物（２２ｍｇ、４７％）を得た。
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.７０−１８１（ｍ，２Ｈ），１.８２−２.０（ｍ，２Ｈ），２.０７−２.１６（ｍ，２Ｈ），２.５６−２.６４（ｍ，１Ｈ），３.４０（”ｔ”，２Ｈ），４.５２（ｄ，２Ｈ），４.８２（ｓ，２Ｈ），６.１０（ｓ，２Ｈ），６.６０（ｔ，１Ｈ），７.１１（ｄ，１Ｈ），７.２０（ｄ，２Ｈ），７.２５−７.３４（ｍ，３Ｈ），７.４３（ｓ，１Ｈ），７.４７（ｄ，１Ｈ），７.５９−７.６６（ｍ，２Ｈ），７.７３（ｓ，１Ｈ），７.８９（ｓ，１Ｈ），８.０−８.０６（ｍ，２Ｈ），８.５８（ｄ，１Ｈ），９.４２（ｄ，１Ｈ），１２.７４（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺６０４。 Example 27
6- (Benzylcarbamoyl-methoxy) -3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid cyclobutylmethyl-amide

[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole-1) prepared in Example 3 according to the procedure described in Example 4 - ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy] acetic acid (40 mg, 0.078 mmol), and using benzylamine (25 mg, 0.23 mmol), over silica gel, CH ₂ Cl as eluent After purification by column chromatography using _{2 /} MeOH (100 / 2.25), the title compound (22 mg, 47%) was obtained.
_{^{1 HNMR (500MHz, CDCl 3)}} δ (ppm): 1.70-181 (m, 2H), 1.82-2.0 (m, 2H), 2.07-2.16 (m, 2H), 2.5-2.64 (m, 1H), 3.40 ("t", 2H), 4.52 (d, 2H), 4.82 (s, 2H), 6.10 (s, 2H) 6.60 (t, 1H), 7.11 (d, 1H), 7.20 (d, 2H), 7.25-7.34 (m, 3H), 7.43 (s, 1H), 7.47 (d, 1H), 7.59-7.66 (m, 2H), 7.73 (s, 1H), 7.89 (s, 1H), 8.0-8.06 (m, 2H), 8.58 (d, 1H), 9.42 (d, 1H), 12.74 (s, 1H); MS (ESI) (M + H) ⁺ 604.

実施例３で製造した［（６−｛［（シクロブチルメチル）アミノ］カルボニル｝−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−イル）オキシ］酢酸（４０ｍｇ、０.０７８ｍｍｏｌ）のジクロロメタン（３ ｍｌ）中の混合物に、トリエチルアミン（３２ｍｇ、０.３１ｍｍｏｌ）、クロロギ酸ネオペンチル（２４ｍｇ、０.１６ｍｍｏｌ）及び４−ジメチルアミノピリジン（６ｍｇ、０.０５ｍｍｏｌ）を、窒素雰囲気下、０℃で加えた。反応混合物を０℃で５０分間撹拌し、次いでジクロロメタンで希釈した。溶液をＮＨ₄Ｃｌ（飽和水溶液）で洗浄し、乾燥し、減圧下で蒸発させた。残留物を、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／２）を用いたシリカゲル上のカラムクロマトグラフィーで精製した後、標題の化合物（４２ｍｇ、９２％）を得た。
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：０.８４（ｓ，９Ｈ），１.７２−１.８４（ｍ，２Ｈ），１.８６−２.０（ｍ，２Ｈ），２.０９−２.１８（ｍ，２Ｈ），２.５５−２.６５（ｍ，１Ｈ），３.４１（”ｔ”，２Ｈ），３.８３（ｓ，２Ｈ），４.８３（ｓ，２Ｈ），６.０９（ｓ，２Ｈ），７.１８（ｄ，１Ｈ），７.４１（ｓ，１Ｈ），７.４５（ｄ，１Ｈ），７.５８−７.６５（ｍ，２Ｈ），７.７１（ｓ，１Ｈ），７.８７（ｄ，１Ｈ），７.９０（ｔ，１Ｈ），８.０１−８.０５（ｍ，１Ｈ），８.５８−８.６０（ｍ，１Ｈ），９.４３（ｄ，１Ｈ），１２.７０（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺５８５.０８。 Example 28
{6- (Cyclobutylmethyl-carbamoyl) -5-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridin-2-yloxy} -acetic acid 2, 2-dimethylpropyl ester

[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} prepared in Example 3 Pyridin-2-yl) oxy] acetic acid (40 mg, 0.078 mmol) in dichloromethane (3 ml) was added to triethylamine (32 mg, 0.31 mmol), neopentyl chloroformate (24 mg, 0.16 mmol) and 4-dimethyl. Aminopyridine (6 mg, 0.05 mmol) was added at 0 ° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0 ° C. for 50 minutes and then diluted with dichloromethane. The solution was washed with NH ₄ Cl (saturated aqueous solution), dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl ₂ / MeOH (100/2) as eluent to give the title compound (42 mg, 92%).
¹ HNMR (500 MHz, CDCl ₃ ) δ (ppm): 0.84 (s, 9H), 1.72-1.84 (m, 2H), 1.86-2.0 (m, 2H), 2. 09-2.18 (m, 2H), 2.55-2.65 (m, 1H), 3.41 ("t", 2H), 3.83 (s, 2H), 4.83 (s, 2H), 6.09 (s, 2H), 7.18 (d, 1H), 7.41 (s, 1H), 7.45 (d, 1H), 7.58-7.65 (m, 2H) ), 7.71 (s, 1H), 7.87 (d, 1H), 7.90 (t, 1H), 8.01-8.05 (m, 1H), 8.58-8.60 ( m, 1H), 9.43 (d, 1H), 12.70 (s, 1H); MS (ESI) (M + H) ⁺ 585.08.

実施例２８に記載された手順に従い、実施例３で製造した［（６−｛［（シクロブチルメチル）アミノ］カルボニル｝−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−イル）オキシ］酢酸（４０ｍｇ、０.０７８ｍｍｏｌ）及びクロロギ酸イソプロピル（０.１２ｍｌ、１Ｍのトルエン溶液：０.１２ｍｍｏｌ）を用いて、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／２.０）を用いた、シリカゲル上のカラムクロマトグラフィーで精製した後、標題の化合物（４２ｍｇ、９２％）を得た。
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２１（ｄ，６Ｈ），１.７２−１.８２（ｍ，２Ｈ），１.８５−２.０２（ｍ，２Ｈ），２.１０−２.１８（ｍ，２Ｈ），２.５６−２.６６（ｍ，１Ｈ），３.４２（”ｔ”，２Ｈ），４.７７（ｓ，２Ｈ），５.０７−５.１６（ｍ，１Ｈ），６.０９（ｓ，２Ｈ），７.１８（ｄ，１Ｈ），７.４３（ｓ，１Ｈ），７.４７（ｄ，１Ｈ），７.５８−７.６６（ｍ，２Ｈ），７.７３（ｓ，１Ｈ），７.８８（ｄ，１Ｈ），７.９５（ｔ，１Ｈ），８.０−８.０５（ｍ，１Ｈ），８.５６−８.６０（ｍ，１Ｈ），９.４３（ｄ，１Ｈ），１２.７０（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５５７。 Example 29
{6- (Cyclobutylmethyl-carbamoyl) -5-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridin-2-yloxy} -acetic acid isopropyl ester

[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole-1) prepared in Example 3 according to the procedure described in Example 28. Eluent using -ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy] acetic acid (40 mg, 0.078 mmol) and isopropyl chloroformate (0.12 ml, 1M toluene solution: 0.12 mmol) After purification by column chromatography on silica gel using CH ₂ Cl _{2 /} MeOH (100 / 2.0) as the title compound (42 mg, 92%) was obtained.
¹ HNMR (500 MHz, CDCl ₃ ) δ (ppm): 1.21 (d, 6H), 1.72-1.82 (m, 2H), 1.85-2.02 (m, 2H), 2. 10-2.18 (m, 2H), 2.56-2.66 (m, 1H), 3.42 ("t", 2H), 4.77 (s, 2H), 5.07-5. 16 (m, 1H), 6.09 (s, 2H), 7.18 (d, 1H), 7.43 (s, 1H), 7.47 (d, 1H), 7.58-7.66 (M, 2H), 7.73 (s, 1H), 7.88 (d, 1H), 7.95 (t, 1H), 8.0-8.05 (m, 1H), 8.56- 8.60 (m, 1H), 9.43 (d, 1H), 12.70 (s, 1H); MS (ESI): (M + H) ⁺ 557.

実施例４に記載した手順に従い、実施例３で製造した［（６−｛［（シクロブチルメチル）アミノ］カルボニル｝−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−イル）オキシ］酢酸（４０ｍｇ、０.０７８ｍｍｏｌ）、及びヒドロキシルアミン塩酸塩（１６ｍｇ、０.２３ｍｍｏｌ）を用いて、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／５〜１００／１５）を用いた、シリカゲル上のカラムクロマトグラフィーで精製した後、標題の化合物（２５ｍｇ、６１％）を得た。
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：１.６９−１.７９（ｍ，２Ｈ），１.８２−１.９５（ｍ，２Ｈ），２.０３−２.１２（ｍ，２Ｈ），２.５４−２.６４（ｍ，１Ｈ），３.３６（ｄ，２Ｈ），４.８０（ｓ，２Ｈ），６.１２（ｓ，２Ｈ），７.１６（ｄ，１Ｈ），７.４５（ｄ，１Ｈ），７.５６（ｓ，１Ｈ），７.５８−７.６３（ｍ，２Ｈ），７.７４（ｄ，２Ｈ），７.８４（ｄ，１Ｈ），８.０７−８.１２（ｍ，１Ｈ），８.４４−８.４９（ｍ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５３０.０２。 Example 30
6-hydroxycarbamoylmethoxy-3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid cyclobutylmethyl-amide

[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole-1-) prepared in Example 3 according to the procedure described in Example 4) (Ilmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy] acetic acid (40 mg, 0.078 mmol) and hydroxylamine hydrochloride (16 mg, 0.23 mmol) as CH ₂ Cl ₂ / After purification by column chromatography on silica gel using MeOH (100/5 to 100/15), the title compound (25 mg, 61%) was obtained.
¹ HNMR (500 MHz, CD ₃ OD) δ (ppm): 1.69-1.79 (m, 2H), 1.82-1.95 (m, 2H), 2.03-2.12 (m, 2H), 2.54-2.64 (m, 1H), 3.36 (d, 2H), 4.80 (s, 2H), 6.12 (s, 2H), 7.16 (d, 1H) ), 7.45 (d, 1H), 7.56 (s, 1H), 7.58-7.63 (m, 2H), 7.74 (d, 2H), 7.84 (d, 1H) , 8.07-8.12 (m, 1H), 8.44-8.49 (m, 1H); MS (ESI): (M + H) ⁺ 530.02.

実施例４に記載された手順に従い、実施例３で製造した［（６−｛［（シクロブチルメチル）アミノ］カルボニル｝−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−イル）オキシ］酢酸（４０ｍｇ、０.０７８ｍｍｏｌ）及びメトキシアミン塩酸塩（２０ｍｇ、０.２３ｍｍｏｌ）を用いて処理した後、標題の化合物（４０ｍｇ、９４％）を得た。
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.７３−１.８２（ｍ，２Ｈ），１.８７−２.０（ｍ，２Ｈ），２.１−２.１８（ｍ，２Ｈ），２.５８−２.６８（ｍ，１Ｈ），３.４５（”ｔ”，２Ｈ），３.８２（ｓ，３Ｈ），４.８１（ｓ，２Ｈ），６.１（ｓ，２Ｈ），７.１４（ｄ，１Ｈ），７.４３（ｓ，１Ｈ），７.４６（ｄ，１Ｈ），７.５９−７.６６（ｍ，２Ｈ），７.７３（ｓ，１Ｈ），７.８８（ｄ，１Ｈ），８.０−８.０８（ｍ，２Ｈ），８.５７（ｄ，１Ｈ），８.８１（ｂｒｓ，１Ｈ），９.４６（ｄ，１Ｈ），１２.７２（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５４４。 Example 31
6- (methoxycarbamoyl-methoxy) -3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid cyclobutylmethyl-amide

[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole-1) prepared in Example 3 according to the procedure described in Example 4 After treatment with -ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy] acetic acid (40 mg, 0.078 mmol) and methoxyamine hydrochloride (20 mg, 0.23 mmol), the title compound (40 mg 94%).
¹ HNMR (500 MHz, CDCl ₃ ) δ (ppm): 1.73-1.82 (m, 2H), 1.87-2.0 (m, 2H), 2.1-2.18 (m, 2H) ), 2.58-2.68 (m, 1H), 3.45 ("t", 2H), 3.82 (s, 3H), 4.81 (s, 2H), 6.1 (s, 2H), 7.14 (d, 1H), 7.43 (s, 1H), 7.46 (d, 1H), 7.59-7.66 (m, 2H), 7.73 (s, 1H) ), 7.88 (d, 1H), 8.0-8.08 (m, 2H), 8.57 (d, 1H), 8.81 (brs, 1H), 9.46 (d, 1H) , 12.72 (s, 1 H); MS (ESI): (M + H) ⁺ 544.

Example 32
{5-[(4-Methyl-naphthalene-1-carbonyl) -amino] -6-[(tetrahydro-pyran-4-ylmethyl) -carbamoyl] -pyridin-2-yloxy} -acetic acid methyl ester

実施例１Ａに記載された方法に従い、６−ヒドロキシ−３−［（４−メチル−ナフタレン−１−カルボニル）−アミノ］−ピリジン−２−カルボン酸（テトラヒドロ−ピラン−４−イルメチル）−アミド（実施例３２Ｂから得た）（１５０ｍｇ、０.３６ｍｍｏｌ）、及びブロモ酢酸メチル（１６４ｍｇ、１.０７ｍｍｏｌ）を用いて、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／１）を用いた、シリカゲル上のカラムクロマトグラフィーで精製した後、標題の化合物（１１０ｍｇ、６３％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４９２.０１。 Example 32A
{5-[(4-Methyl-naphthalene-1-carbonyl) -amino] -6-[(tetrahydro-pyran-4-ylmethyl) -carbamoyl] -pyridin-2-yloxy} -acetic acid methyl ester

According to the method described in Example 1A, 6-hydroxy-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide ( (From Example 32B) (150 mg, 0.36 mmol) and methyl bromoacetate (164 mg, 1.07 mmol) on silica gel using CH ₂ Cl ₂ / MeOH (100/1) as eluent. After purification by column chromatography, the title compound (110 mg, 63%) was obtained.
MS (ESI): (M + H) ^<+ > 492.01.

実施例２Ｂに記載された方法に従い、６−メトキシ−３−［（４−メチル−ナフタレン−１−カルボニル）−アミノ］−ピリジン−２−カルボン酸（テトラヒドロ−ピラン−４−イルメチル）−アミド（実施例３２Ｃから得た）（６８５ｍｇ、１.５８ｍｍｏｌ）及びピリジン塩酸塩（１４.５ｇ、０.１２６ｍｏｌ）を用いて、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／２.５〜１００／５）を用いた、シリカゲル上のカラムクロマトグラフィーで精製した後、標題の化合物（４６０ｍｇ、６９％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ ４２０.０１。 Example 32B
6-Hydroxy-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide

Following the procedure described in Example 2B, 6-methoxy-3-[(4-methyl-naphthalen-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide ( (From Example 32C) (685 mg, 1.58 mmol) and pyridine hydrochloride (14.5 g, 0.126 mol) and CH ₂ Cl _{2 /} MeOH (100 / 2.5-100 / 5) as eluent. The title compound (460 mg, 69%) was obtained after purification by column chromatography on silica gel using
MS (ESI): (M + H) ^<+> 420.01.

実施例２Ｃに記載された手順に従い、実施例１Ｅで製造した６−メトキシ−３−［（４−メチル−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチル（５７０ｍｇ、１.６３ｍｍｏｌ）、及び１−（テトラヒドロ−２Ｈ−ピラン−４−イル）メタンアミン（１.７５ｇ、１５.１９ｍｍｏｌ）を用いて処理した後、標題の化合物を（６９０ｍｇ、９８％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ ５３４.０１。 Example 32C
6-Methoxy-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide

Following the procedure described in Example 2C, methyl 6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate prepared in Example 1E (570 mg, 1.63 mmol), and After treatment with 1- (tetrahydro-2H-pyran-4-yl) methanamine (1.75 g, 15.19 mmol), the title compound was obtained (690 mg, 98%).
MS (ESI): (M + H) ^<+ > 534.01.

Example 33
6-Carbamoylmethoxy-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide

実施例４に記載された手順に従い、｛５−［（４−メチル−ナフタレン−１−カルボニル）−アミノ］−６−［（テトラヒドロ−ピラン−４−イルメチル）−カルバモイル］−ピリジン−２−イルオキシ｝−酢酸（実施例３３Ｂから得た）（９２ｍｇ、０.１９ｍｍｏｌ）及び塩化アンモニウム（５２ｍｇ、０.９６ｍｍｏｌ）を用いて処理した後、標題の化合物（８７ｍｇ、９５％）を得た。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.３−１.４６（ｍ，２Ｈ），１.６−１.７２（ｍ，２Ｈ），１.７７−１.９３（ｍ，１Ｈ），２.７４（ｓ，３Ｈ），３.２９（”ｔ”，２Ｈ），３.３８（”ｔ”，２Ｈ），３.９１−４.０４（ｍ，２Ｈ），４.７４（ｓ，２Ｈ），５.５９（ｂｒｓ，１Ｈ），６.２４（ｂｒｓ，１Ｈ），７.１２（ｄ，１Ｈ），７.３９（ｄ，１Ｈ），７.５３−７.６２（ｍ，２Ｈ），７.７９（ｄ，１Ｈ），８.０−８.１６（ｍ，２Ｈ），８.５２−８.６０（ｍ，１Ｈ），９.４４（ｄ，１Ｈ），１２.５３（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４７７.０２。 Example 33A
6-Carbamoylmethoxy-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide

Following the procedure described in Example 4, {5-[(4-Methyl-naphthalen-1-carbonyl) -amino] -6-[(tetrahydro-pyran-4-ylmethyl) -carbamoyl] -pyridin-2-yloxy } -Acetic acid (obtained from Example 33B) (92 mg, 0.19 mmol) and ammonium chloride (52 mg, 0.96 mmol) gave the title compound (87 mg, 95%).
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.3-1.46 (m, 2H), 1.6-1.72 (m, 2H), 1.77-1.93 (m, 1H ), 2.74 (s, 3H), 3.29 ("t", 2H), 3.38 ("t", 2H), 3.91-4.04 (m, 2H), 4.74 ( s, 2H), 5.59 (brs, 1H), 6.24 (brs, 1H), 7.12 (d, 1H), 7.39 (d, 1H), 7.53-7.62 (m , 2H), 7.79 (d, 1H), 8.0-8.16 (m, 2H), 8.52-8.60 (m, 1H), 9.44 (d, 1H), 12. 53 (s, 1 H); MS (ESI): (M + H) ⁺ 477.02.

実施例３に記載された手順に従い、｛５−［（４−メチル−ナフタレン−１−カルボニル）−アミノ］−６−［（テトラヒドロ−ピラン−４−イルメチル）−カルバモイル］−ピリジン−２−イルオキシ｝−酢酸メチルエステル（実施例３２から得られた）（１１０ｍｇ、０.２２ｍｍｏｌ）及びＮａＯＨ（２７ｍｇ、０.６７ｍｍｏｌ）を用いて処理した後、標題の化合物（９４ｍｇ、８６％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ ４８８.０２。 Example 33B
{5-[(4-Methyl-naphthalene-1-carbonyl) -amino] -6-[(tetrahydro-pyran-4-ylmethyl) -carbamoyl] -pyridin-2-yloxy} -acetic acid

Following the procedure described in Example 3, {5-[(4-Methyl-naphthalen-1-carbonyl) -amino] -6-[(tetrahydro-pyran-4-ylmethyl) -carbamoyl] -pyridin-2-yloxy } -Acetic acid methyl ester (obtained from Example 32) (110 mg, 0.22 mmol) and NaOH (27 mg, 0.67 mmol) gave the title compound (94 mg, 86%).
MS (ESI): (M + H) ^<+ > 488.02.

実施例１Ａに記載された手順に従い、６−ヒドロキシ−３−［（４−メチル−ナフタレン−１−カルボニル）−アミノ］−ピリジン−２−カルボン酸（テトラヒドロ−ピラン−４−イルメチル）−アミド（実施例３２Ｂから得た）（１４８ｍｇ、０.３５ｍｍｏｌ）、及び２−ブロモエタノール（２２０ｍｇ、１.７５ｍｍｏｌ）を用いて、溶離液としてＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／２）を用いた、シリカゲル上のカラムクロマトグラフィーで精製した後、標題の化合物（８４ｍｇ、５１％）を得た。
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.３５−１.４５（ｍ，２Ｈ），１.６２−１.７０（ｍ，２Ｈ），１.８３−１.９２（ｍ，１Ｈ），２.７７（ｓ，３Ｈ），３.２（”ｔ”，２Ｈ），３.４（”ｔ”，２Ｈ），３.９７−４.０２（ｍ，２Ｈ），４.０３−４.０７（ｍ，２Ｈ），４.４２−４.４６（ｍ，２Ｈ），７.０９（ｄ，１Ｈ），７.４２（ｄ，１Ｈ），７.５７−７.６２（ｍ，２Ｈ），７.８２（ｄ，１Ｈ），８.０２−８.１０（ｍ，１Ｈ），８.２０（ｔ，１Ｈ），８.５７−８.６３（ｍ，１Ｈ），９.４０（ｄ，１Ｈ），１２.４９（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）＋４６４。 Example 34
6- (2-Hydroxy-ethoxy) -3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide

Following the procedure described in Example 1A, 6-hydroxy-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide ( Silica gel, obtained from Example 32B) (148 mg, 0.35 mmol) and 2-bromoethanol (220 mg, 1.75 mmol) with CH ₂ Cl ₂ / MeOH (100/2) as eluent. After purification by column chromatography above, the title compound (84 mg, 51%) was obtained.
¹ HNMR (500 MHz, CDCl ₃ ) δ (ppm): 1.35-1.45 (m, 2H), 1.62-1.70 (m, 2H), 1.83-1.92 (m, 1H ), 2.77 (s, 3H), 3.2 ("t", 2H), 3.4 ("t", 2H), 3.97-4.02 (m, 2H), 4.03- 4.07 (m, 2H), 4.42-4.46 (m, 2H), 7.09 (d, 1H), 7.42 (d, 1H), 7.57-7.62 (m, 2H), 7.82 (d, 1H), 8.02-8.10 (m, 1H), 8.20 (t, 1H), 8.57-8.63 (m, 1H), 9.40. (D, 1H), 12.49 (s, 1H); MS (ESI): (M + H) +464.

６−（２−ヒドロキシ−エトキシ）−３−［（４−メチル−ナフタレン−１−カルボニル）−アミノ］−ピリジン−２−カルボン酸（テトラヒドロ−ピラン−４−イルメチル）−アミド（実施例３４から得た）（８４ｍｇ、０.１８ｍｍｏｌ）のＣＣｌ₄（１０ｍｌ）中の混合物に、Ｎ−ブロモスクシンイミド（３５ｍｇ、０.２ｍｍｏｌ）及び過酸化ベンゾイル（９ｍｇ、０.０４ｍｍｏｌ）を加えた。反応混合物を３時間還流し、次いで濾過した。濾液をジクロロメタンで希釈し、ＮａＨＣＯ₃（飽和水溶液）で洗浄し、乾燥し、減圧下で蒸発させた。残留物をメタノール（５ｍｌ）中に懸濁させ、ナトリウムチオメトキシド（５０ｍｇ）を加えた。反応混合物を室温で７２時間撹拌し、次いで溶媒を減圧下で蒸発させた。残留物をジクロロメタンに溶解し、４ＭのＨＣｌ（水溶液）で洗浄し、乾燥し、減圧下で蒸発させた。残留物をアセトニトリル及び酢酸アンモニウム緩衝液（２０／８０〜８０／２０）を溶離液として用いた分取型ＨＰＬＣで精製し、標題の化合物（４ｍｇ、５％）を得た。
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２５−１.４５（ｍ，２Ｈ），１.５５−１.７（ｍ，２Ｈ），１.８０−１.９０（ｍ，１Ｈ），３.２７−３.３２（ｍ，２Ｈ），３.３３−４.０（ｍ，２Ｈ），３.４８（ｓ，３Ｈ），３.９４−４.０５（ｍ，４Ｈ），３.３９−４.４３（ｍ，２Ｈ），４.９５（ｓ，２Ｈ），７.０７（ｄ，１Ｈ），７.５５−７.６１（ｍ，３Ｈ），７.８４（ｄ，１Ｈ），８.１０−８.１４（ｍ，１Ｈ），８.１７（ｔ，１Ｈ），８.５１−８.５７（ｍ，１Ｈ），９.３８（ｄ，１Ｈ），１２.５０（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４９４.０２。 Example 35
6- (2-Hydroxy-ethoxy) -3-[(4-methoxymethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide

6- (2-Hydroxy-ethoxy) -3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide (from Example 34) obtained) (84 mg, to a mixture of CCl ₄ in (10ml) of 0.18 mmol), was added N- bromosuccinimide (35 mg, 0.2 mmol) and benzoyl peroxide (9mg, 0.04mmol). The reaction mixture was refluxed for 3 hours and then filtered. The filtrate was diluted with dichloromethane, washed with NaHCO ₃ (saturated aqueous solution), dried and evaporated under reduced pressure. The residue was suspended in methanol (5 ml) and sodium thiomethoxide (50 mg) was added. The reaction mixture was stirred at room temperature for 72 hours and then the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed with 4M HCl (aq), dried and evaporated under reduced pressure. The residue was purified by preparative HPLC using acetonitrile and ammonium acetate buffer (20 / 80-80 / 20) as eluents to give the title compound (4 mg, 5%).
¹ HNMR (500 MHz, CDCl ₃ ) δ (ppm): 1.25 to 1.45 (m, 2H), 1.55 to 1.7 (m, 2H), 1.80 to 1.90 (m, 1H) ), 3.27-3.32 (m, 2H), 3.33-4.0 (m, 2H), 3.48 (s, 3H), 3.94-4.05 (m, 4H), 3.39-4.43 (m, 2H), 4.95 (s, 2H), 7.07 (d, 1H), 7.55-7.61 (m, 3H), 7.84 (d, 1H), 8.10-8.14 (m, 1H), 8.17 (t, 1H), 8.51-8.57 (m, 1H), 9.38 (d, 1H), 12.50 (S, 1 H); MS (ESI): (M + H) ⁺ 494.02.

Examples 36 and 37
6-methanesulfonyl-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide, and 6-methanesulfinyl-3- [ (4-Methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide

３−［（４−メチル−ナフタレン−１−カルボニル）−アミノ］−６−メチルスルファニル−ピリジン−２−カルボン酸（テトラヒドロ−ピラン−４−イルメチル）−アミド（実施例３６及び３７：Ｂから得た）（０.５ｇ、１.１１ｍｍｏｌ）及びＫ₂ＣＯ₃（０.４６ｇ、３.３４ ｍｍｏｌ）のジクロロメタン（１０ｍｌ）中の混合物に、３−クロロ過安息香酸（０.３９ｇ、ＣＨ₂Ｃｌ₂（６ｍｌ）に溶解した）の溶液を滴下しながら加えた。反応混合物を室温で７０分間撹拌した。更に、３−クロロ過安息香酸（７０ｍｇ、ＣＨ₂Ｃｌ₂（３ｍｌ）に溶解した）を加え、反応混合物を更に２０分間撹拌した。反応混合物をジクロロメタンで希釈した。水を加えた後、有機相を分離し、ＮａＨＣＯ₃（飽和水溶液）で洗浄し、乾燥し、そして減圧下で蒸発させた。残留物を、ＣＨ₂Ｃｌ₂／ＭｅＯＨ（１００／２.５）を溶離液として用いた、シリカゲル上のカラムクロマトグラフィーで精製し、標題の化合物を得た：
６−メタンスルホニル−３−［（４−メチル−ナフタレン−１−カルボニル）−アミノ］−ピリジン−２−カルボン酸（テトラヒドロ−ピラン−４−イルメチル）−アミド（１９１ｍｇ、３６％）：
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.３０−１.４６（ｍ，２Ｈ），１.６０−１.７０（ｍ，２Ｈ），１.８０−１.９６（ｍ，１Ｈ），２.７７（ｓ，３Ｈ），３.１９（ｓ，３Ｈ），３.３０−３.４３（ｍ，４Ｈ），３.９３−４.０２（ｍ，２Ｈ），７.４４（ｄ，１Ｈ），７.５７−７.６５（ｍ，２Ｈ），７.８３（ｄ，１Ｈ），８.０４−８.１２（ｍ，１Ｈ），８.２４−８.３４（ｍ，２Ｈ），８.５５−８.６３（ｍ，１Ｈ），９.６９（ｄ，１Ｈ），１３.０２（ｓ，１Ｈ）；及び、
６−メタンスルフィニル−３−［（４−メチル−ナフタレン−１−カルボニル）−アミノ］−ピリジン−２−カルボン酸（テトラヒドロ−ピラン−４−イルメチル）−アミド（３１２ｍｇ、６０％）：
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２４−１.４８（ｍ，２Ｈ），１.５８−１.７２（ｍ，２Ｈ），１.７８−１.９６（ｍ，１Ｈ），２.７７（ｓ，３Ｈ），２.８５（ｓ，３Ｈ），３.２９−３.４３（ｍ，４Ｈ），３.９３−４.０３（ｍ，２Ｈ），７.４３（ｄ，１Ｈ），７.５６−７.６５（ｍ，２Ｈ），７.８３（ｄ，１Ｈ），８.０４−８.１２（ｍ，１Ｈ），８.１６−８.２７（ｍ，２Ｈ），８.５５−８.６４（ｍ，１Ｈ），９.６９（ｄ，１Ｈ），１２.８４（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）＋４６６。 Examples 36 and 37: A
6-methanesulfonyl-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide, and 6-methanesulfinyl-3- [ (4-Methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide

3-[(4-Methyl-naphthalene-1-carbonyl) -amino] -6-methylsulfanyl-pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide (Examples 36 and 37: obtained from B) ) (0.5 g, 1.11 mmol) and K ₂ CO ₃ (0.46 g, 3.34 mmol) in dichloromethane (10 ml) were added to 3-chloroperbenzoic acid (0.39 g, CH ₂ Cl ₂ (dissolved in 6 ml) was added dropwise. The reaction mixture was stirred at room temperature for 70 minutes. Further 3-chloroperbenzoic acid (70 mg, dissolved in CH ₂ Cl ₂ (3 ml)) was added and the reaction mixture was stirred for an additional 20 minutes. The reaction mixture was diluted with dichloromethane. After adding water, the organic phase was separated, washed with NaHCO ₃ (saturated aqueous solution), dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using CH ₂ Cl _{2 /} MeOH (100 / 2.5) as eluent to give the title compound:
6-Methanesulfonyl-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide (191 mg, 36%):
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.30 to 1.46 (m, 2H), 1.60 to 1.70 (m, 2H), 1.80 to 1.96 (m, 1H) ), 2.77 (s, 3H), 3.19 (s, 3H), 3.30-3.43 (m, 4H), 3.93-4.02 (m, 2H), 7.44 ( d, 1H), 7.57-7.65 (m, 2H), 7.83 (d, 1H), 8.04-8.12 (m, 1H), 8.24-8.34 (m, 2H), 8.55-8.63 (m, 1H), 9.69 (d, 1H), 13.02 (s, 1H); and
6-Methanesulfinyl-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide (312 mg, 60%):
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.24-1.48 (m, 2H), 1.58-1.72 (m, 2H), 1.78-1.96 (m, 1H) ), 2.77 (s, 3H), 2.85 (s, 3H), 3.29-3.43 (m, 4H), 3.93-4.03 (m, 2H), 7.43 ( d, 1H), 7.56-7.65 (m, 2H), 7.83 (d, 1H), 8.04-8.12 (m, 1H), 8.16-8.27 (m, 2H), 8.55-8.64 (m, 1H), 9.69 (d, 1H), 12.84 (s, 1H); MS (ESI): (M + H) +466.

実施例３６及び３７：Ｃから得た、６−クロロ−３−［（４−メチル−ナフタレン−１−カルボニル）−アミノ］−ピリジン−２−カルボン酸（テトラヒドロ−ピラン−４−イルメチル）−アミド（１ｇ、２.２８ｍｍｏｌ）及びナトリウムチオメトキシド（０.４８ｇ、６.８５ｍｍｏｌ）の無水ＤＭＦ（１５ｍｌ）中の混合物を、マイクロウエーブで、１００℃で１５分間加熱した。水を室温で加えた。生成した沈澱物を集め、水で希釈し、風乾した。固体をエーテル中で懸濁させ、次いで濾過して取除き、減圧下で乾燥し、標題の化合物（０.９ｇ、９４％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ ４４９.９７。 Examples 36 and 37: B
3-[(4-Methyl-naphthalene-1-carbonyl) -amino] -6-methylsulfanyl-pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide

Examples 36 and 37: 6-chloro-3-[(4-methyl-naphthalen-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide obtained from C A mixture of (1 g, 2.28 mmol) and sodium thiomethoxide (0.48 g, 6.85 mmol) in anhydrous DMF (15 ml) was heated in a microwave at 100 ° C. for 15 minutes. Water was added at room temperature. The resulting precipitate was collected, diluted with water and air dried. The solid was suspended in ether, then filtered off and dried under reduced pressure to give the title compound (0.9 g, 94%).
MS (ESI): (M + H) ^<+ > 449.97.

実施例２Ｃに記載された手順に従い、実施例２１Ｄで製造した６−クロロ−３−［（４−メチル−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチル（３ｇ、８.４６ｍｍｏｌ）、及び１−（テトラヒドロ−２Ｈ−ピラン−４−イル）メタンアミン（４.８７ｇ、４２.２８ｍｍｏｌ）を用いて処理した後、標題の化合物（３.１４ｇ、８５％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４３８。 Examples 36 and 37: C
6-Chloro-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide

Following the procedure described in Example 2C, methyl 6-chloro-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate prepared in Example 21D (3 g, 8.46 mmol), and After treatment with 1- (tetrahydro-2H-pyran-4-yl) methanamine (4.87 g, 42.28 mmol), the title compound (3.14 g, 85%) was obtained.
MS (ESI): (M + H) ^<+> 438.

実施例１０Ｂで製造した６−ヒドロキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（６２ｍｇ、０.１３ｍｍｏｌ）、２−（２−クロロ−エトキシ）−エタノール（１１６ｍｇ、０.９３ｍｍｏｌ）及び炭酸銀（１７１ｍｇ、０.６２ｍｍｏｌ）のＤＭＦ（３ｍｌ）中の混合物を、マイクロウエーブで、１２０℃で２.５時間加熱した。更に、２−（２−クロロ−エトキシ）−エタノール（８００ｍｇ）を加え、反応混合物を、マイクロウエーブで、１３０℃で４時間更に加熱した。反応混合物をジクロロメタンで希釈し、次いで濾過した。溶媒を減圧下で蒸発させた。残留物をジクロロメタンに溶解し、水で洗浄し、乾燥し、減圧下で蒸発させ、次いでアセトニトリル及び酢酸アンモニウム緩衝液（２０／８０〜７０／３０）を溶離液として用いた分取型ＨＰＬＣで精製し、標題の化合物（２８ｍｇ、３８％）を得た。
¹ＨＮＭＲ（３００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２２−１.４８（ｍ，２Ｈ），１.５８−１.７２（ｍ，２Ｈ），１.７６−１.９３（ｍ，１Ｈ），３.２５−３.４４（ｍ，４Ｈ），３.６６−３.８３（ｍ，４Ｈ），３.８８−４.０２（ｍ，４Ｈ），４.４２−４.５０（ｍ，２Ｈ），６.０７（ｓ，２Ｈ），７.０８（ｄ，１Ｈ），７.４１（ｓ，１Ｈ），７.４２（ｄ，１Ｈ），７.５４−７.６６（ｍ，２Ｈ），７.７３（ｓ，１Ｈ），７.８４（ｄ，１Ｈ），８.０（ｄ，１Ｈ），８.２０（ｔ，１Ｈ），８.５４（ｄ，１Ｈ），９.３５（ｄ，１Ｈ），１２.５７（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５７５.１２。 Example 38
6- [2- (2-Hydroxy-ethoxy) -ethoxy] -3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid Acid (tetrahydro-pyran-4-ylmethyl) -amide

6-Hydroxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] prepared in Example 10B Amino} pyridine-2-carboxamide (62 mg, 0.13 mmol), 2- (2-chloro-ethoxy) -ethanol (116 mg, 0.93 mmol) and silver carbonate (171 mg, 0.62 mmol) in DMF (3 ml). The mixture was heated in a microwave at 120 ° C. for 2.5 hours. Further 2- (2-chloro-ethoxy) -ethanol (800 mg) was added and the reaction mixture was further heated at 130 ° C. for 4 hours in a microwave. The reaction mixture was diluted with dichloromethane and then filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, washed with water, dried, evaporated under reduced pressure and then purified by preparative HPLC using acetonitrile and ammonium acetate buffer (20 / 80-70 / 30) as eluent. To give the title compound (28 mg, 38%).
¹ HNMR (300 MHz, CDCl ₃ ) δ (ppm): 1.22-1.48 (m, 2H), 1.58-1.72 (m, 2H), 1.76-1.93 (m, 1H ), 3.25-3.44 (m, 4H), 3.66-3.83 (m, 4H), 3.88-4.02 (m, 4H), 4.42-4.50 (m , 2H), 6.07 (s, 2H), 7.08 (d, 1H), 7.41 (s, 1H), 7.42 (d, 1H), 7.54-7.66 (m, 2H), 7.73 (s, 1H), 7.84 (d, 1H), 8.0 (d, 1H), 8.20 (t, 1H), 8.54 (d, 1H), 9. 35 (d, 1 H), 12.57 (s, 1 H); MS (ESI): (M + H) ⁺ 575.12.

Example 39
6-methoxy-3-({4-[(4-methylpiperazin-1-yl) methyl] -1-naphthoyl} amino) -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

実施例３９Ｂで製造した、３−｛［４−（ブロモメチル）−１−ナフトイル］アミノ｝−６−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（３８.５ｍｇ、０.０７５ｍｍｏｌ）を、ＮａＨ（７ｍｇ、０.２９ｍｍｏｌ）及び１−メチルピペラジン（１５.６ｍｇ、０.１６ｍｏｌ）のアセトニトリル（２ｍｌ）溶液に加え、反応混合物を窒素雰囲気下で２時間撹拌した。混合物を水及びＤＣＭで希釈し、ＭｇＳＯ₄で乾燥し、濾過し、減圧下で濃縮した。粗製の生成物を、12+M Biotageカラムとトルエン／ＥｔＯＨ＝３０／１にＥｔ₃Ｎ（１０％）を加えた溶離液を用いたシリカゲルフラッシュクロマトグラフィーで精製し、そしてその後、分取型ＨＰＬＣを用いて、６−メトキシ−３−（｛４−［（４−メチルピペラジン−１−イル）メチル］−１−ナフトイル｝アミノ）−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（１.２ｍｇ、３％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２０−１.４０（ｍ，４Ｈ），１.６０−１.６６（ｍ，１Ｈ），１.７７−１.８８（ｍ，２Ｈ），２.３０−２.６０（ｍ，１０Ｈ），３.２７−３.３９（ｍ，４Ｈ），３.９０−３.９８（ｍ，６Ｈ），７.１０（ｄ，１Ｈ），７.４７−７.５５（ｍ，３Ｈ），７.７６（ｓ，１Ｈ），８.２１−８.２７（ｍ，１Ｈ），８.３０−８.３４（ｍ，１Ｈ），８.４７−８.５２（ｍ，１Ｈ），８.３３（ｄ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５３２.０９。 Example 39A
6-methoxy-3-({4-[(4-methylpiperazin-1-yl) methyl] -1-naphthoyl} amino) -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

3-{[4- (Bromomethyl) -1-naphthoyl] amino} -6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (38.5 mg) prepared in Example 39B. , 0.075 mmol) was added to a solution of NaH (7 mg, 0.29 mmol) and 1-methylpiperazine (15.6 mg, 0.16 mol) in acetonitrile (2 ml) and the reaction mixture was stirred under a nitrogen atmosphere for 2 h. The mixture was diluted with water and DCM, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using a 12 + M Biotage column and an eluent of toluene / EtOH = 30/1 plus Et ₃ N (10%) and then preparative HPLC. 6-methoxy-3-({4-[(4-methylpiperazin-1-yl) methyl] -1-naphthoyl} amino) -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine- 2-Carboxamide (1.2 mg, 3%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.20-1.40 (m, 4H), 1.60-1.66 (m, 1H), 1.77-1.88 (m, 2H) ), 2.30-2.60 (m, 10H), 3.27-3.39 (m, 4H), 3.90-3.98 (m, 6H), 7.10 (d, 1H), 7.47-7.55 (m, 3H), 7.76 (s, 1H), 8.21-8.27 (m, 1H), 8.30-8.34 (m, 1H), 8. 47-8.52 (m, 1 H), 8.33 (d, 1 H); MS (ESI): (M + H) ⁺ 532.09.

実施例３９Ｃで製造した３−｛［４−（メチル）−１−ナフトイル］アミノ｝−６−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（１４４ｍｇ、０.３３ｍｍｏｌ）のＣＣｌ₄（７ｍｌ）中の混合物に、Ｎ−ブロモスクシンイミド（６５ｍｇ、０.３６ｍｍｏｌ）及び過酸化ベンゾイル（８ｍｇ、０.０３３ｍｍｏｌ）を加えた。反応混合物を窒素雰囲気下で１.５時間還流した。有機溶媒を減圧下で除去し、粗製の生成物をＤＣＭに溶解し、溶離液としてヘプタン／ＥｔＯＡｃ＝２／１を用い、シリカのパッドを通して濾過し、３−｛［４−（ブロモメチル）−１−ナフトイル］アミノ｝−６−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（１４３ｍｇ、８４％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ−Ｈ）^- ５１１.７６。 Example 39B
3-{[4- (Bromomethyl) -1-naphthoyl] amino} -6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

3-{[4- (Methyl) -1-naphthoyl] amino} -6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (144 mg, 0. in CCl ₄ mixture in (7 ml) in 33 mmol), N-bromosuccinimide (65 mg, 0.36 mmol) and benzoyl peroxide (8 mg, 0.033 mmol) was added. The reaction mixture was refluxed for 1.5 hours under a nitrogen atmosphere. The organic solvent was removed under reduced pressure and the crude product was dissolved in DCM and filtered through a pad of silica using heptane / EtOAc = 2/1 as eluent to give 3-{[4- (bromomethyl) -1 -Naphthoyl] amino} -6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (143 mg, 84%) was obtained.
^{MS (ESI) :( M-H} ) - 511.76.

実施例１Ｅで製造した６−メトキシ−３−［（４−メチル−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチル（１.０ｇ、２.８５ｍｍｏｌ）の無水ＤＭＦ（２０ｍｌ）中の混合物に、４−アミノメチルテトラヒドロピラン（１.３１ｇ、１１.４２ｍｍｏｌ）を加えた。反応混合物を、窒素雰囲気下、８０℃で１.５時間撹拌した。反応混合物をＥｔＯＡｃ及び水で希釈した。有機相を１ＭのＨＣｌで洗浄し、無水ＭｇＳＯ₄で乾燥し、次いで濾過し、減圧下で濃縮した。粗製の生成物を、12+M Biotageカラムとヘプタン／ＥｔＯＡｃ＝３／１の溶離液を用いたシリカゲルフラッシュクロマトグラフィーで精製し、３−｛［４−（メチル）−１−ナフトイル］アミノ｝−６−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（１.２ｇ、９７％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.３０−１.４１（ｍ，３Ｈ），１.６０−１.６６（ｍ，２Ｈ），１.７５−１.８８（ｍ，２Ｈ），２.７１（ｓ，３Ｈ），３.２６−３.４０（ｍ，４Ｈ），３.９８（ｓ，３Ｈ），７.００（ｄ，１Ｈ），７.３６（ｄ，１Ｈ），７.５２−７.５６（ｍ，２Ｈ），７.７６（ｄ，１Ｈ），８.００−８.０５（ｍ，１Ｈ），８.２０−８.２５（ｍ，１Ｈ），８.５３−８.５８（ｍ，１Ｈ），９.３３（ｓ，１Ｈ），１２.４３（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４３４.０５。 Example 39C
3-{[4- (Methyl) -1-naphthoyl] amino} -6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

To a mixture of methyl 6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate (1.0 g, 2.85 mmol) prepared in Example 1E in anhydrous DMF (20 ml). 4-aminomethyltetrahydropyran (1.31 g, 11.42 mmol) was added. The reaction mixture was stirred at 80 ° C. under a nitrogen atmosphere for 1.5 hours. The reaction mixture was diluted with EtOAc and water. The organic phase was washed with 1M HCl, dried over anhydrous MgSO ₄ , then filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using a 12 + M Biotage column and an eluent of heptane / EtOAc = 3/1 to give 3-{[4- (methyl) -1-naphthoyl] amino}- 6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (1.2 g, 97%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.30 to 1.41 (m, 3H), 1.60 to 1.66 (m, 2H), 1.75 to 1.88 (m, 2H) ), 2.71 (s, 3H), 3.26-3.40 (m, 4H), 3.98 (s, 3H), 7.00 (d, 1H), 7.36 (d, 1H) 7.52-7.56 (m, 2H), 7.76 (d, 1H), 8.00-8.05 (m, 1H), 8.20-8.25 (m, 1H), 8 .53-8.58 (m, 1H), 9.33 (s, 1H), 12.43 (s, 1H); MS (ESI): (M + H) ⁺ 434.05.

Example 40
6-methoxy-3-{[4- (morpholin-4-ylmethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

実施例３９Ｂで製造した３−｛［４−（ブロモメチル）−１−ナフトイル］アミノ｝−６−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（３８.５ｍｇ、０.０７５ｍｍｏｌ）を、ＮａＨ（７ｍｇ、０.２９ｍｍｏｌ）及びモルホリン（１３.６ｍｇ、０.１６ｍｍｏｌ）のアセトニトリル（２ｍｌ）溶液に加え、反応溶液を窒素雰囲気下で２時間撹拌した。混合物を水及びＤＣＭで希釈し、ＭｇＳＯ₄で乾燥し、濾過し、減圧下で濃縮した。粗製の生成物を12+M Biotageカラムとトルエン／ＥｔＯＨ＝２０／１の溶離液を用いたシリカゲルフラッシュクロマトグラフィーで精製し、６−メトキシ−３−｛［４−（モルホリン−４−イルメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（３４.５ｍｇ、８９％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：０.９７−１.０４（ｍ，１Ｈ），１.３２−１.４４（ｍ，３Ｈ），１.７１−１.７８（ｍ，２Ｈ），１.９５−２.０７（ｍ，１Ｈ），２.６６（ｂｒｓ，３Ｈ），３.３６−３.４５（ｍ，３Ｈ），３.６０（ｓ，３Ｈ），３.７４−３.７９（ｍ，３Ｈ），３.９５−４.０１（ｍ，２Ｈ），４.１４（ｓ，１Ｈ），４.１６（ｓ，２Ｈ），７.３６（ｄ，１Ｈ），７.７６−７.８２（ｍ，２Ｈ），８.０６（ｄ，１Ｈ），８.６０−８.７０（ｍ，２Ｈ），９.２２−９.２９（ｍ，１Ｈ），９.４４（ｄ，１Ｈ），１２.９５（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５１９.０６。 Example 40A
6-methoxy-3-{[4- (morpholin-4-ylmethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

3-{[4- (Bromomethyl) -1-naphthoyl] amino} -6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (38.5 mg, prepared in Example 39B) 0.075 mmol) was added to a solution of NaH (7 mg, 0.29 mmol) and morpholine (13.6 mg, 0.16 mmol) in acetonitrile (2 ml) and the reaction solution was stirred under a nitrogen atmosphere for 2 hours. The mixture was diluted with water and DCM, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using 12 + M Biotage column and eluent of toluene / EtOH = 20/1 to give 6-methoxy-3-{[4- (morpholin-4-ylmethyl)- 1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (34.5 mg, 89%) was obtained.
¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 0.97-1.04 (m, 1H), 1.32-1.44 (m, 3H), 1.71-1.78 (m, 2H) ), 1.95-2.07 (m, 1H), 2.66 (brs, 3H), 3.36-3.45 (m, 3H), 3.60 (s, 3H), 3.74- 3.79 (m, 3H), 3.95-4.01 (m, 2H), 4.14 (s, 1H), 4.16 (s, 2H), 7.36 (d, 1H), 7 .76-7.82 (m, 2H), 8.06 (d, 1H), 8.60-8.70 (m, 2H), 9.22-9.29 (m, 1H), 9.44 (D, 1H), 12.95 (s, 1H); MS (ESI): (M + H) ^<+ > 519.06.

Example 41
6-[(Ethylamino) sulfonyl] -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

実施例４１Ｂで製造した、６−（ベンジルチオ）−３−｛［４−（メトキシメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（４３ｍｇ、０.０７７ｍｍｏｌ）のＤＣＭ（１ｍｌ）溶液、水（０.１６ｍｌ）及び濃ＨＣｌ（２０μｌ） を０℃に冷却した。次亜塩素酸ナトリウム（５％、２０μｌ）を溶液に滴下しながら加えた。反応溶液を０℃で４０分間撹拌し、対応するスルホニルクロリドを得た。得られた混合物を、相分離器を通して、ＤＣＭ（１ｍｌ）中に過剰のエチルアミンを含む反応フラスコに濾過した。有機溶媒を減圧下で除去し、粗製の生成物を分取型ＨＰＬＣで精製し、６−［（エチルアミノ）スルホニル］−３−｛［４−（メトキシメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（３.７ｍｇ、９％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.１３（ｔ，３Ｈ），１.２９−１.４０（ｍ，２Ｈ），１.５９−１.６５（ｍ，２Ｈ），１.８０−１.９０（ｍ，１），３.０８−３.１７（ｍ，２Ｈ），３.２８−３.３８（ｍ，３Ｈ），３.４８（ｓ，３Ｈ），３.９１−３.９８（ｍ，２Ｈ），４.７８−４.８２（ｍ，１Ｈ），４.９４（ｓ，２Ｈ），７.５６−７.６２（ｍ，３Ｈ），７.８６（ｄ，１Ｈ），８.３６−８.８.４１（ｍ，２Ｈ），８.５２−８.５５（ｍ，１Ｈ），９.６１（ｄ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５４１.１４。 Example 41A
6-[(Ethylamino) sulfonyl] -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

6- (Benzylthio) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (prepared in Example 41B) A solution of 43 mg, 0.077 mmol) in DCM (1 ml), water (0.16 ml) and concentrated HCl (20 μl) was cooled to 0 ° C. Sodium hypochlorite (5%, 20 μl) was added dropwise to the solution. The reaction solution was stirred at 0 ° C. for 40 minutes to obtain the corresponding sulfonyl chloride. The resulting mixture was filtered through a phase separator into a reaction flask containing excess ethylamine in DCM (1 ml). The organic solvent was removed under reduced pressure and the crude product was purified by preparative HPLC to give 6-[(ethylamino) sulfonyl] -3-{[4- (methoxymethyl) -1-naphthoyl] amino}- N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (3.7 mg, 9%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.13 (t, 3H), 1.29-1.40 (m, 2H), 1.59-1.65 (m, 2H), 1. 80-1.90 (m, 1), 3.08-3.17 (m, 2H), 3.28-3.38 (m, 3H), 3.48 (s, 3H), 3.91- 3.98 (m, 2H), 4.78-4.82 (m, 1H), 4.94 (s, 2H), 7.56-7.62 (m, 3H), 7.86 (d, 1H), 8.36-8.8.41 (m, 2H), 8.52-8.55 (m, 1H), 9.61 (d, 1H); MS (ESI): (M + H) ⁺ 541 .14.

ＮａＨ（７１.５ｍｇ、２.９８ｍｍｏｌ）のＤＭＦ（２５ｍｌ）溶液及びベンジルメルカプタン（３７０ｍｇ、２.９８ｍｍｏｌ）を滴下しながら加えた。滴下を終えた後、実施例４１Ｃで製造した、６−クロロ−３−｛［４−（メトキシメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（４６５ｍｇ、０.９９ｍｍｏｌ）を加えた。反応混合物を室温で２時間撹拌した。水及びＤＣＭを加え、溶液を相分離器を通して濾過し、減圧下で濃縮し、分取型ＨＰＬＣで精製して、６−（ベンジルチオ）−３−｛［４−（メトキシメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（３３５ｍｇ、６１％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.１９−１.３０（ｍ，３Ｈ），１.６０−１.７５（ｍ，１Ｈ），３.１５（ｔ，２Ｈ），３.２５−３.３９（ｍ，３Ｈ），３.４５（ｓ，３Ｈ），３.８７−３.９５（ｍ，２Ｈ），４.３５（ｓ，２Ｈ），４.９２（ｓ，２Ｈ），７.１２−７.１７（ｍ，１Ｈ），７.２９−７.３４（ｍ，２Ｈ），７.３８−７.４３（ｍ，３Ｈ），７.５４−５７（ｍ，３Ｈ），７.８０（ｓ，１Ｈ），７.９６−８.０２（ｍ，１Ｈ），８.０８−８.１３（ｍ，１Ｈ），８.４７−８.５４（ｍ，１Ｈ），９.２４（ｄ，１Ｈ），１２.５４（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ−Ｈ）^-５５４.０４。 Example 41B
6- (Benzylthio) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

NaH (71.5 mg, 2.98 mmol) in DMF (25 ml) and benzyl mercaptan (370 mg, 2.98 mmol) were added dropwise. After completion of the dropwise addition, 6-chloro-3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine- prepared in Example 41C 2-Carboxamide (465 mg, 0.99 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water and DCM are added and the solution is filtered through a phase separator, concentrated under reduced pressure and purified by preparative HPLC to give 6- (benzylthio) -3-{[4- (methoxymethyl) -1-naphthoyl. Amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (335 mg, 61%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.19-1.30 (m, 3H), 1.60-1.75 (m, 1H), 3.15 (t, 2H), 3. 25-3.39 (m, 3H), 3.45 (s, 3H), 3.87-3.95 (m, 2H), 4.35 (s, 2H), 4.92 (s, 2H) 7.12-7.17 (m, 1H), 7.29-7.34 (m, 2H), 7.38-7.43 (m, 3H), 7.54-57 (m, 3H) 7.80 (s, 1H), 7.96-8.02 (m, 1H), 8.08-8.13 (m, 1H), 8.47-8.54 (m, 1H), 9 .24 (d, 1H), 12.54 (s, 1H); MS (ESI): (M−H) ⁻ 554.04.

実施例４１Ｄで製造した３−｛［４−（ブロモメチル）−１−ナフトイル］アミノ｝−６−クロロ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（１.２７ｇ、２.４７ｍｍｏｌ）のナトリウムメトキシド溶液を、室温で終夜撹拌した。有機溶媒を減圧下で除去し、残留物をＤＣＭ及び水で希釈し、有機相を乾燥し、濃縮し、そして25+M Biotageカラムとトルエン／ＥｔＯＡｃ＝９／１の溶離液を用いたシリカゲルフラッシュクロマトグラフィーで精製し、６−クロロ−３−｛［４−（メトキシメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（０.４７ｇ、４０％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２９−１.４１（ｍ，２Ｈ），１.６０−１.６７（ｍ，２Ｈ），１.８０−１.９０（ｍ，１Ｈ），３.２５−３.３９（ｍ，４Ｈ），３.４６（ｓ，３Ｈ），３.９２−３.９９（ｍ，２Ｈ），４.９４（ｓ，３Ｈ），７.５０（ｄ，１Ｈ），７.５５−７.６０（ｍ，３Ｈ），７.８３（ｄ，１Ｈ），８.０９−８.１４（ｍ，１Ｈ），８.２１−８.２７（ｍ，１Ｈ），８.４６−８.５４（ｍ，１Ｈ），８.４９−８.５５（ｍ，１Ｈ），９.４２（ｄ，１Ｈ），１２.６８（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４６８.２１。 Example 41C
6-chloro-3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

3-{[4- (Bromomethyl) -1-naphthoyl] amino} -6-chloro-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (1.27 g, prepared in Example 41D) 2.47 mmol) of sodium methoxide was stirred at room temperature overnight. The organic solvent is removed under reduced pressure, the residue is diluted with DCM and water, the organic phase is dried, concentrated and silica gel flash using a 25 + M Biotage column and an eluent of toluene / EtOAc = 9/1. Purification by chromatography gave 6-chloro-3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (0.47 g). 40%).
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.29-1.41 (m, 2H), 1.60-1.67 (m, 2H), 1.80-1.90 (m, 1H ), 3.25-3.39 (m, 4H), 3.46 (s, 3H), 3.92-3.99 (m, 2H), 4.94 (s, 3H), 7.50 ( d, 1H), 7.55-7.60 (m, 3H), 7.83 (d, 1H), 8.09-8.14 (m, 1H), 8.21-8.27 (m, 1H), 8.46-8.54 (m, 1H), 8.49-8.55 (m, 1H), 9.42 (d, 1H), 12.68 (s, 1H); MS (ESI ): (M + H) ⁺ 468.21.

３−｛［４−（ブロモメチル）−１−ナフトイル］アミノ｝−６−クロロ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミドを、実施例３９Ｂと同様の方法で、収率１００％で製造した。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５１８.００。 Example 41D
3-{[4- (Bromomethyl) -1-naphthoyl] amino} -6-chloro-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

3-{[4- (Bromomethyl) -1-naphthoyl] amino} -6-chloro-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide was prepared in the same manner as Example 39B. Produced in 100% yield.
MS (ESI): (M + H) ^<+ > 518.00.

６−クロロ−３−［（４−メチル−１−ナフトイル）アミノ］ピリジン−２−カルボン酸メチルを実施例２１Ｄと同様の方法で製造し、そして６−クロロ−３−［（４−メチル−１−ナフトイル）アミノ］−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミドも実施例３９Ｃと同様の方法で製造した。粗製の生成物を、Biotageカラムとヘプタン／ＥｔＯＡｃ＝２／１の溶離液を用いたシリカゲルフラッシュクロマトグラフィーで精製し、収率９３％を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２９−１.４１（ｍ，２Ｈ），１.６０−１.６６（ｍ，２Ｈ），１.８０−１.９０（ｍ，１Ｈ），２.７３（ｓ，３Ｈ），３.２６−３.４０（ｍ，４Ｈ），３.９２−３.９９（ｍ，２Ｈ），７.３８（ｓ，１Ｈ），７.５０（ｄ，１Ｈ），７.５４−７.５９（ｍ，１Ｈ），７.７８（ｄ，２Ｈ），８.０２−８.０７（ｍ，１Ｈ），８.２０−８.２７（ｍ，１Ｈ），８.５１−８.５７（ｍ，１Ｈ），９.４１（ｄ，１Ｈ），１２.６８（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４３８.０７。 Example 41E
6-chloro-3-[(4-methyl-1-naphthoyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

Methyl 6-chloro-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate was prepared in a similar manner to Example 21D and 6-chloro-3-[(4-methyl- 1-naphthoyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide was also prepared in the same manner as in Example 39C. The crude product was purified by silica gel flash chromatography using a Biotage column and an eluent of heptane / EtOAc = 2/1 to give 93% yield.
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.29-1.41 (m, 2H), 1.60-1.66 (m, 2H), 1.80-1.90 (m, 1H) ), 2.73 (s, 3H), 3.26-3.40 (m, 4H), 3.92-3.99 (m, 2H), 7.38 (s, 1H), 7.50 ( d, 1H), 7.54-7.59 (m, 1H), 7.78 (d, 2H), 8.02-8.07 (m, 1H), 8.20-8.27 (m, 1H), 8.51-8.57 (m, 1H), 9.41 (d, 1H), 12.68 (s, 1H); MS (ESI): (M + H) ⁺ 438.07.

Examples 42 and 43
6- (Benzylsulfonyl) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide and 6- (benzylsulfonyl) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

実施例４１Ｂで製造した、６−（ベンジルチオ）−３−｛［４−（メトキシメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（１２４ｍｇ、０.２２ｍｍｏｌ）のＤＣＭ（３ｍｌ）溶液に、３−クロロ過安息香酸（５８ｍｇ、０.３３ｍｍｏｌ）のクロロホルム（１ｍｌ）溶液を、０℃で、滴下しながら加えた。反応混合物を０℃で３０分間撹拌した。水を加え、溶液を相分離器を通して濾過し、減圧下で濃縮し、分取型ＨＰＬＣで精製し、６−（ベンジルスルフィニル）−３−｛［４−（メトキシメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（６５ｍｇ、５１％）、及び６−（ベンジルスルホニル）−３−｛［４−（メトキシメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（１５ｍｇ、１２％）を得た。
６−（ベンジルスルフィニル）−３−｛［４−（メトキシメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド：
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２７−１.４０（ｍ，３Ｈ），１.５８−１.６２（ｍ，１Ｈ），１.７５−１.８６（ｍ，１Ｈ），３.１３−３.２１（ｍ，１Ｈ），３.３０−３.４０（ｍ，３Ｈ），３.４８（ｓ，３Ｈ），３.９２−４.００（ｍ，２Ｈ），４.１４−４.２４（ｍ，２Ｈ），４.９３（ｓ，３Ｈ），６.９７−７.０２.（ｍ，２Ｈ），７.２５−７.３０（ｍ，３Ｈ），７.５５−７.６１（ｍ，３Ｈ），７.８４（ｄｄ，２Ｈ），７.９９−８.０５（ｍ，１Ｈ），８.０９−８.１４（ｍ，１Ｈ），８.５１−８.５７（ｍ，１Ｈ），９.９５（ｄ，１Ｈ），１２.８４（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５７２.３３；及び、
６−（ベンジルスルホニル）−３−｛［４−（メトキシメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド：
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２８−１.４０（ｍ，３Ｈ），１.５８−１.６２（ｍ，１Ｈ），１.８７−１.８９（ｍ，１Ｈ），３.２５−３.４０（ｍ，４Ｈ），３.４８（ｓ，３Ｈ），３.９２−３.９９（ｍ，２Ｈ），４.４９（ｓ，２Ｈ），４.９４（ｓ，２Ｈ），７.１２−７.１７（ｍ，２Ｈ），７.２５−７.３５（ｍ，３Ｈ），７.５５−７.６３（ｍ，３Ｈ），７.９０（ｄｄ，２Ｈ），８，０９−８.１８（ｍ，２Ｈ），８.５０−８.５６（ｍ，１Ｈ），９.５１（ｄ，２Ｈ），１３.０２（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５８８.３４。 Examples 42 and 43: A
6- (benzylsulfonyl) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide, and 6- (benzylsulfonyl) ) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

6- (Benzylthio) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (prepared in Example 41B) To a solution of 124 mg, 0.22 mmol) in DCM (3 ml), a solution of 3-chloroperbenzoic acid (58 mg, 0.33 mmol) in chloroform (1 ml) was added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes. Water is added and the solution is filtered through a phase separator, concentrated under reduced pressure, purified by preparative HPLC, and 6- (benzylsulfinyl) -3-{[4- (methoxymethyl) -1-naphthoyl] amino. } -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (65 mg, 51%), and 6- (benzylsulfonyl) -3-{[4- (methoxymethyl) -1-naphthoyl] Amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (15 mg, 12%) was obtained.
6- (Benzylsulfinyl) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide:
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.27 to 1.40 (m, 3H), 1.58 to 1.62 (m, 1H), 1.75 to 1.86 (m, 1H) ), 3.13-3.21 (m, 1H), 3.30-3.40 (m, 3H), 3.48 (s, 3H), 3.92-4.00 (m, 2H), 4.14-4.24 (m, 2H), 4.93 (s, 3H), 6.97-7.02. (M, 2H), 7.25-7.30 (m, 3H), 7 .55-7.61 (m, 3H), 7.84 (dd, 2H), 7.99-8.05 (m, 1H), 8.09-8.14 (m, 1H), 8.51 −8.57 (m, 1H), 9.95 (d, 1H), 12.84 (s, 1H); MS (ESI): (M + H) ⁺ 572.33; and
6- (Benzylsulfonyl) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide:
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.28-1.40 (m, 3H), 1.58-1.62 (m, 1H), 1.87-1.89 (m, 1H) ), 3.25-3.40 (m, 4H), 3.48 (s, 3H), 3.92-3.99 (m, 2H), 4.49 (s, 2H), 4.94 ( s, 2H), 7.12-7.17 (m, 2H), 7.25-7.35 (m, 3H), 7.55-7.63 (m, 3H), 7.90 (dd, 2H), 8, 09-8.18 (m, 2H), 8.50-8.56 (m, 1H), 9.51 (d, 2H), 13.02 (s, 1H); MS (ESI ): (M + H) ⁺ 588.34.

Example 44
6-[(Tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazin-2-yl 3,3,3-trifluoropropane-1-sulfonic acid

炭酸銀（３０ｍｇ、０.１０８ｍｍｏｌ）を、実施例４４Ｂで製造した６−ヒドロキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピラジン−２−カルボキサミド（１５ｍｇ、０.０３１ｍｍｏｌ）のアセトニトリル（１０ｍｌ）溶液に加え、そして混合物を５分間撹拌した。次いで、３，３，３−トリフルオロプロパン−１−スルホニルクロリド（１８ｍｇ、０.０９２ｍｍｏｌ）を加え、反応混合物を２.５時間還流した。反応溶液に、ＣＨ₂Ｃｌ₂／ＭｅＯＨ（１／１、１０ｍｌ）の混合物を加えてクエンチし、固体物質を濾過し、濾液を蒸発させた。残留物をＣＨ₂Ｃｌ₂に溶解し、飽和のＮａＨＣＯ₃水溶液及び飽和のＮａＣｌ水溶液で洗浄し、乾燥（Ｎａ₂ＳＯ₄）し、蒸発させた。残留物をフラッシュクロマトグラフィー（ＣＨ₂Ｃｌ₂／ＭｅＯＨ＝４０／１）で精製し、３，３，３−トリフルオロプロパン−１−スルホン酸６−［（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）カルバモイル］−５−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピラジン−２−イル（２０ｍｇ、定量的）を得た。
¹ＨＮＭＲ（６００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.３３−１.４０（ｍ，２Ｈ），１.６０−１.６４（ｍ，２Ｈ），１.８０−１.８８（ｍ，１Ｈ），２.８９−２.９７（ｍ，２Ｈ），３.３１−３.３９（ｍ，４Ｈ），３.６８−３.７２（ｍ，２Ｈ），３.９５−３.９９（ｍ，２Ｈ），６.０９（ｓ，２Ｈ），７.４１（ｄ，１Ｈ），７.４３（ｓ，１Ｈ），７.６０−７.６５（ｍ，２Ｈ），７.７１（ｓ，１Ｈ），７.７９（ｂｒｔ，１Ｈ），７.９０（ｄ，１Ｈ），８.０３−８.０５（ｍ，１Ｈ），８.６１−８.６３（ｍ，１Ｈ），８.６９（ｓ，１Ｈ），１２.６３（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺６４８.０。 Example 44A
3,3,3-trifluoropropane-1-sulfonic acid 6-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] -5-{[4- (1H-1,2,3-triazole-1- Ylmethyl) -1-naphthoyl] amino} pyrazin-2-yl

Silver carbonate (30 mg, 0.108 mmol) was prepared from 6-hydroxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-) prepared in Example 44B. Triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2-carboxamide (15 mg, 0.031 mmol) was added to a solution of acetonitrile (10 ml) and the mixture was stirred for 5 minutes. 3,3,3-trifluoropropane-1-sulfonyl chloride (18 mg, 0.092 mmol) was then added and the reaction mixture was refluxed for 2.5 hours. The reaction solution was quenched by addition of a mixture of CH ₂ Cl ₂ / MeOH (1/1, 10 ml), the solid material was filtered and the filtrate was evaporated. The residue was dissolved in CH ₂ Cl ₂ and washed with saturated aqueous NaHCO ₃ and saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by flash chromatography _{(CH 2 Cl 2 / MeOH =} 40/1) , and 3,3,3-trifluoro-1-sulfonic acid 6 - [(tetrahydro -2H- pyran-4-ylmethyl) Carbamoyl] -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazin-2-yl (20 mg, quantitative) was obtained.
¹ HNMR (600 MHz, CDCl ₃ ) δ (ppm): 1.33-1.40 (m, 2H), 1.60-1.64 (m, 2H), 1.80-1.88 (m, 1H) ), 2.89-2.97 (m, 2H), 3.31-3.39 (m, 4H), 3.68-3.72 (m, 2H), 3.95-3.99 (m) , 2H), 6.09 (s, 2H), 7.41 (d, 1H), 7.43 (s, 1H), 7.60-7.65 (m, 2H), 7.71 (s, 1H), 7.79 (brt, 1H), 7.90 (d, 1H), 8.03-8.05 (m, 1H), 8.61-8.63 (m, 1H), 8.69 (S, 1 H), 12.63 (s, 1 H); MS (ESI): (M + H) ⁺ 648.0.

実施例４４Ｃで製造した、６−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピラジン−２−カルボキサミド（１４２ｍｇ、０.２８３ｍｍｏｌ）及びピリジン塩酸塩（２.７８ｇ、２４.１ｍｍｏｌ）の混合物を、１５０℃で２.５時間加熱した。室温で水を加え、生成した沈殿物を集め、水で洗浄し、乾燥した。濾液を４℃で終夜冷却し、更に生成した沈澱物を集め、水で洗浄し、乾燥した。集めた沈殿物を逆相ＨＰＬＣ（２０→１００％ＭｅＣＮ／０.１ＭのＮＨ₄ＯＡｃ水溶液）で精製し、６−ヒドロキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピラジン−２−カルボキサミド（１５ｍｇ、１１％）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４８８.０。 Example 44B
6-hydroxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2- Carboxamide

6-Methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl prepared in Example 44C A mixture of amino} pyrazine-2-carboxamide (142 mg, 0.283 mmol) and pyridine hydrochloride (2.78 g, 24.1 mmol) was heated at 150 ° C. for 2.5 hours. Water was added at room temperature and the resulting precipitate was collected, washed with water and dried. The filtrate was cooled at 4 ° C. overnight, and the resulting precipitate was collected, washed with water and dried. The collected precipitate was purified by reverse phase HPLC (20 → 100% MeCN / 0.1M aqueous NH ₄ OAc) to give 6-hydroxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[ 4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2-carboxamide (15 mg, 11%) was obtained.
MS (ESI): (M + H) ^<+> 488.0.

実施例４４Ｄで製造した６−メトキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピラジン−２−カルボン酸メチル（１８５ｍｇ、０.２９５ｍｍｏｌ）及び１−（テトラヒドロ−２Ｈ−ピラン−４−イル）メタンアミン（２５８ｍｇ、２.２４ｍｍｏｌ）の対応するＴＦＡ塩のＤＭＦ（３ｍｌ）溶液を、１２０℃で終夜（１４時間）加熱した。更に１−（テトラヒドロ−２Ｈ−ピラン−４−イル）メタンアミン（１５０ｍｇ、１.３０ｍｍｏｌ）を加え、反応混合物を９０℃で更に１６時間撹拌した。反応溶液を減圧下で蒸発させ、残留物を逆相ＨＰＬＣ（３０→１００％ＭｅＣＮ／０.１ＭのＮＨ₄ＯＡｃ水溶液）で精製し、６−メトキシ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピラジン−２−カルボキサミド（１５８ｍｇ、定量的）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.３０−１.４１（ｍ，２Ｈ），１.５９−１.６５（ｍ，２Ｈ），１.７８−１.８９（ｍ，１Ｈ），３.２９−３.３９（ｍ，４Ｈ），３.９３−４.００（ｍ，２Ｈ），４.００（ｓ，３Ｈ），６.０５（ｓ，２Ｈ），７.３７（ｓ，１Ｈ），７.４０（ｄ，１Ｈ），７.５４−７.６１（ｍ，２Ｈ），７.６７（ｓ，１Ｈ），７.８７（ｄ，１Ｈ），７.９４−８.００（ｍ，２Ｈ９，８.４４（ｓ，１Ｈ），８.５９−８.６３（ｍ，１Ｈ），１２.１９（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５０２.０。 Example 44C
6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2- Carboxamide

Methyl 6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2-carboxylate prepared in Example 44D (185 mg, 0.0. 295 mmol) and 1- (tetrahydro-2H-pyran-4-yl) methanamine (258 mg, 2.24 mmol) in DMF (3 ml) in the corresponding TFA salt were heated at 120 ° C. overnight (14 hours). More 1- (tetrahydro-2H-pyran-4-yl) methanamine (150 mg, 1.30 mmol) was added and the reaction mixture was stirred at 90 ° C. for a further 16 hours. The reaction solution was evaporated under reduced pressure and the residue was purified by reverse phase HPLC (30 → 100% MeCN / 0.1M aqueous NH ₄ OAc) to give 6-methoxy-N- (tetrahydro-2H-pyran-4- Ilmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2-carboxamide (158 mg, quantitative) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.30 to 1.41 (m, 2H), 1.59 to 1.65 (m, 2H), 1.78 to 1.89 (m, 1H) ), 3.29-3.39 (m, 4H), 3.93-4.00 (m, 2H), 4.00 (s, 3H), 6.05 (s, 2H), 7.37 ( s, 1H), 7.40 (d, 1H), 7.54-7.61 (m, 2H), 7.67 (s, 1H), 7.87 (d, 1H), 7.94-8 .00 (m, 2H9, 8.44 (s, 1H), 8.59-8.63 (m, 1H), 12.19 (s, 1H); MS (ESI): (M + H) ⁺ 502.0 .

Ｎ−ブロモスクシンイミン（４５６ｍｇ、２.５６ｍｍｏｌ）及び過酸化ベンゾイル（６１ｍｇ、０.２５ｍｍｏｌ）を、実施例２５Ｆ又は実施例４４Ｅで製造した６−メトキシ−３−［（４−メチル−１−ナフトイル）アミノ］ピラジン−２−カルボン酸メチルの、ＣＣｌ₄（６０ｍｌ）中の温（〜７７℃）懸濁液に加えた。反応混合物を２.５時間還流した。追加の過酸化ベンゾイル（触媒量、スパチュラの先端量）を加え、反応混合物を還流下で更に１２時間加熱した。溶媒を除去した後、残留物をＥｔＯＡｃに溶解し、水及び飽和のＮａＣｌ水溶液で洗浄し、乾燥（Ｎａ₂ＳＯ₄）し、蒸発させ、粗製のベンジルブロミド（１.１４ｇ）を得た。アセトニトリル（５０ｍｌ）に還流下で溶解したこの粗製のベンジルブロミド（１.１３ｇ）に、１，２，３−トリアゾール（０.４８７ｍｌ、８.４０ｍｍｏｌ）を加え、得られた混合物を還流下で終夜（１６時間）加熱した。次いで、溶液を減圧下で蒸発させ、そして残留物を逆相ＨＰＬＣ（３０→１００％ＭｅＣＮ／０.１ＭのＮＨ₄ＯＡｃ水溶液；次いで、３０→１００％ＭｅＣＮ／０.１５％ＴＦＡ水溶液）で精製し、６−メトキシ−３−｛［４−（１Ｈ−１，２，３−トリアゾール−１−イルメチル）−１−ナフトイル］アミノ｝ピラジン−２−カルボン酸メチルを、その対応するＴＦＡ塩（８８ｍｇ：純品；３３３ｍｇ：若干不純物あり；全収率：〜３９％）として得た。ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ ４１８.９。 Example 44D
Methyl 6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2-carboxylate

N-bromosuccinimine (456 mg, 2.56 mmol) and benzoyl peroxide (61 mg, 0.25 mmol) were prepared according to 6-methoxy-3-[(4-methyl-1- To a warm (˜77 ° C.) suspension of methyl naphthoyl) amino] pyrazine-2-carboxylate in CCl ₄ (60 ml). The reaction mixture was refluxed for 2.5 hours. Additional benzoyl peroxide (catalytic amount, tip of spatula) was added and the reaction mixture was heated at reflux for an additional 12 hours. After removal of the solvent, the residue was dissolved in EtOAc, washed with water and saturated aqueous NaCl, dried (Na ₂ SO ₄ ) and evaporated to give crude benzyl bromide (1.14 g). To this crude benzyl bromide (1.13 g) dissolved in acetonitrile (50 ml) under reflux, 1,2,3-triazole (0.487 ml, 8.40 mmol) was added and the resulting mixture was refluxed overnight. Heated (16 hours). The solution was then evaporated under reduced pressure and the residue was purified by reverse phase HPLC (30 → 100% MeCN / 0.1M aqueous NH ₄ OAc; then 30 → 100% MeCN / 0.15% aqueous TFA). 6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2-carboxylate with its corresponding TFA salt (88 mg : Pure product; 333 mg: some impurities; overall yield: ~ 39%). MS (ESI): (M + H) ^<+ > 418.9.

４−メチル−１−ナフトイルクロリド（３.３７ｇ、１６.５ｍｍｏｌ）の ＣＨＣｌ₃（６ｍｌ）溶液を、実施例２５Ｇで得た３−アミノ−６−メトキシピラジン−２−カルボン酸メチル（６０４ｍｇ、３.３０ｍｍｏｌ）及び４−ジメチルアミノピリジン（４０ｍｇ、０.３３ｍｇ）のピリジン（１０ｍｌ）中の混合物に加えた。得られた反応混合物を、５０℃で終夜（１４時間）撹拌した。ＮａＨＣＯ₃（固体）（１.３９ｇ、１６.５ｍｍｏｌ）を加え、ガスの発生が止んだ後、反応混合物を蒸発させた。残留物をＣＨ₂Ｃｌ₂及び水の間で分配し、次いで有機相を飽和のＮａＨＣＯ₃水溶液及び水で洗浄し、乾燥（Ｎａ₂ＳＯ₄）し、減圧下で蒸発させた。残留物をフラッシュクロマトグラフィー（トルエン／ＥｔＯＨ＝３０／１）で精製し、ジアシル化ピラジン誘導体（１.４８ｇ）を得た。
ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ ５１９.９。
このジアシル化ピラジン誘導体を、１，４−ジオキサン（１０ｍｌ）及び２−プロパノールに〜１００℃で溶解した。ヒドラジン・一水和物（０.１３８ｍｌ、２.８５ｍｍｏｌ）を加え、反応混合物を３０分間還流した。反応混合物を減圧下で蒸発させ、そして、残留物をフラッシュカラムクロマトグラフィー（トルエン／ＥｔＯＨ＝１５／１）で精製し、６−メトキシ−３−［（４−メチル−１−ナフトイル）アミノ］ピラジン−２−カルボン酸メチル（４６１ｍｇ、全収率：７６％）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺ ３５２.１。 Example 44E
Methyl 6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyrazine-2-carboxylate

A solution of 4-methyl-1-naphthoyl chloride (3.37 g, 16.5 mmol) in CHCl ₃ (6 ml) was added methyl 3-amino-6-methoxypyrazine-2-carboxylate (604 mg, obtained in Example 25G). 3.30 mmol) and 4-dimethylaminopyridine (40 mg, 0.33 mg) in a mixture in pyridine (10 ml). The resulting reaction mixture was stirred at 50 ° C. overnight (14 hours). NaHCO ₃ (solid) (1.39 g, 16.5 mmol) was added and after the evolution of gas ceased, the reaction mixture was evaporated. The residue was partitioned between CH ₂ Cl ₂ and water, then the organic phase was washed with saturated aqueous NaHCO ₃ and water, dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The residue was purified by flash chromatography (toluene / EtOH = 30/1) to obtain a diacylated pyrazine derivative (1.48 g).
MS (ESI): (M + H) ^<+ > 519.9.
This diacylated pyrazine derivative was dissolved in 1,4-dioxane (10 ml) and 2-propanol at ˜100 ° C. Hydrazine monohydrate (0.138 ml, 2.85 mmol) was added and the reaction mixture was refluxed for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue was purified by flash column chromatography (toluene / EtOH = 15/1) to give 6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyrazine Methyl-2-carboxylate (461 mg, overall yield: 76%); MS (ESI): (M + H) ⁺ 352.1.

実施例１５及び１６：Ａ〜Ｂに類似の手順を用いて、Ｎ，Ｎ−ジメチルプロパ−２−イン−１−アミン（０.２９８ｍｌ、２.７７ｍｍｏｌ）及び実施例１５及び１６Ｃで得た、粗製の３−｛［４−（アジドメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル（２００ｍｇ、０.５５３ｍｍｏｌ）を用いて、Ｎ−（シクロブチルメチル）−３−｛［４−（｛５−［（ジメチルアミノ）メチル］−１Ｈ−１，２，３−トリアゾール−１−イル｝メチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（４１ｍｇ、粗製アジドから１５％）：
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤ₃ＣＮ）δ（ｐｐｍ）：１.７３−１.８１（ｍ，２Ｈ），１.８４−１.９５（ｍ，２Ｈ），２.２０（ｓ，６Ｈ），２.５５−２.６５（ｍ，１Ｈ），３.３７−３.４１（ｍ，２Ｈ），３.４７（ｓ，２Ｈ），６.２０（ｓ，２Ｈ），７.２３（ｄ，１Ｈ），７.６３−７.７３（ｍ，４Ｈ），７.８６（ｄ，１Ｈ），８.３３−８.３７（ｍ，１Ｈ），８.５３（ｄ，１Ｈ），８.６１（ｂｒｓ，１Ｈ），９.３３（ｄ，１Ｈ），１３.００（ｂｒｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４９８.１；及び、
Ｎ−（シクロブチルメチル）−３−｛［４−（｛４−［（ジメチルアミノ）メチル］−１Ｈ−１，２，３−トリアゾール−１−イル｝メチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボキサミド（５０ｍｇ、粗製アジドから１８％）：
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤ₃ＣＮ）δ（ｐｐｍ）：１.６８−１.７９（ｍ，２Ｈ），１.８１−１.９０（ｍ，２Ｈ），１.９８−２.０６（ｍ，２Ｈ，２.１８（ｓ，６Ｈ），３.３３−３.３７（ｍ，２Ｈ），３.５６（ｓ，２Ｈ），６.０８（ｓ，２Ｈ），７.４３（ｄ，１Ｈ），７.５９−７.６９（ｍ，４Ｈ），７.８６（ｄ，１Ｈ），８.１７−８.２１（ｍ，１Ｈ），８.３２（ｄｄ，１Ｈ），８.４７−８.５１（ｍ，１Ｈ），８.５８（ｂｒｓ，１Ｈ），９.２９（ｄｄ，１Ｈ），１２.９８（ｂｒｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４９８.１
を得た。 Examples 45 and 46
N- (cyclobutylmethyl) -3-{[4-({5-[(dimethylamino) methyl] -1H-1,2,3-triazol-1-yl} methyl) -1-naphthoyl] amino} pyridine -2-carboxamide; and N- (cyclobutylmethyl) -3-{[4-({4-[(dimethylamino) methyl] -1H-1,2,3-triazol-1-yl} methyl) -1 -Naphthoyl] amino} pyridine-2-carboxamide

Examples 15 and 16: Using procedures similar to AB, obtained with N, N-dimethylprop-2-yn-1-amine (0.298 ml, 2.77 mmol) and Examples 15 and 16C. Using crude methyl 3-{[4- (azidomethyl) -1-naphthoyl] amino} pyridine-2-carboxylate (200 mg, 0.553 mmol), N- (cyclobutylmethyl) -3-{[4- ({5-[(Dimethylamino) methyl] -1H-1,2,3-triazol-1-yl} methyl) -1-naphthoyl] amino} pyridine-2-carboxamide (41 mg, 15% from crude azide):
¹ HNMR (500 MHz, CD ₃ CN) δ (ppm): 1.73-1.81 (m, 2H), 1.84-1.95 (m, 2H), 2.20 (s, 6H), 2 0.55-2.65 (m, 1H), 3.37-3.41 (m, 2H), 3.47 (s, 2H), 6.20 (s, 2H), 7.23 (d, 1H) ), 7.63-7.73 (m, 4H), 7.86 (d, 1H), 8.33-8.37 (m, 1H), 8.53 (d, 1H), 8.61 ( brs, 1H), 9.33 (d, 1H), 13.00 (brs, 1H); MS (ESI): (M + H) ⁺ 498.1; and
N- (cyclobutylmethyl) -3-{[4-({4-[(dimethylamino) methyl] -1H-1,2,3-triazol-1-yl} methyl) -1-naphthoyl] amino} pyridine 2-Carboxamide (50 mg, 18% from crude azide):
¹ HNMR (400 MHz, CD ₃ CN) δ (ppm): 1.68-1.79 (m, 2H), 1.81-1.90 (m, 2H), 1.98-2.06 (m, 2H, 2.18 (s, 6H), 3.33-3.37 (m, 2H), 3.56 (s, 2H), 6.08 (s, 2H), 7.43 (d, 1H) 7.59-7.69 (m, 4H), 7.86 (d, 1H), 8.17-8.21 (m, 1H), 8.32 (dd, 1H), 8.47-8 .51 (m, 1H), 8.58 (brs, 1H), 9.29 (dd, 1H), 12.98 (brs, 1H); MS (ESI): (M + H) ⁺ 498.1
Got.

実施例１５及び１６：Ａ〜Ｂに類似の手順を用いて、過剰の３，３，３−トリフルオロプロパ−１−イン（〜１ｍｌ、−７８℃で濃縮した）、及び実施例１５及び１６Ｃで得た３−｛［４−（アジドメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル（１１９ｍｇ、０.３２９ｍｍｏｌ）を用い、Ｎ−（シクロブチルメチル）−３−［（４−｛［４−（トリフルオロメチル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボキサミド（２０ｍｇ、粗製アジドから１２％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６８−１.７７（ｍ，２Ｈ），１.８３−１.９４（ｍ，２Ｈ），２.０３−２.１２（ｍ，２Ｈ），２.５０−２.６２（ｍ，１Ｈ），３.３７−３.４２（ｍ，２Ｈ），６.０６（ｓ，２Ｈ），７.４９−７.５４（ｍ，２Ｈ），７.５７−７.６４（ｍ，３Ｈ），７.８８（ｄ，１Ｈ），７.９３−７.９８（ｍ，１Ｈ），８.２８（ｄ，１Ｈ），８.４０−８.４８（ｍ，１Ｈ），８.５３−８.５７（ｍ，１Ｈ），９.３６（ｄ，１Ｈ），１２.９５（ｂｒｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５０９.０。 Example 47
N- (cyclobutylmethyl) -3-[(4-{[4- (trifluoromethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2 -Carboxamide

Examples 15 and 16: Using procedures similar to AB, excess 3,3,3-trifluoroprop-1-yne (˜1 ml, concentrated at −78 ° C.), and Examples 15 and 16C 3-{[4- (azidomethyl) -1-naphthoyl] amino} methyl pyridine-2-carboxylate (119 mg, 0.329 mmol) obtained in 1 above was used and N- (cyclobutylmethyl) -3-[(4- {[4- (Trifluoromethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2-carboxamide (20 mg, 12% from crude azide) was obtained. .
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.68-1.77 (m, 2H), 1.83-1.94 (m, 2H), 2.03-2.12 (m, 2H) ), 2.50-2.62 (m, 1H), 3.37-3.42 (m, 2H), 6.06 (s, 2H), 7.49-7.54 (m, 2H), 7.57-7.64 (m, 3H), 7.88 (d, 1H), 7.93-7.98 (m, 1H), 8.28 (d, 1H), 8.40-8. 48 (m, 1H), 8.53-8.57 (m, 1H), 9.36 (d, 1H), 12.95 (brs, 1H); MS (ESI): (M + H) ⁺ 509.0 .

実施例１５及び１６：Ａ〜Ｂに類似の手順を用いて、Matthews［Matthews; McCarthy; J. Org. Chem.; 1990, 55, 2973-2975］らの手順から得た、１−フルオロビニルフェニルスルホン（２３５ｍｇ、１.２６ｍｍｏｌ）、及び実施例１５及び１６：Ｃから得た粗製の３−｛［４−（アジドメチル）−１−ナフトイル］アミノ｝ピリジン−２−カルボン酸メチル（２２８ｍｇ、０.６３１ｍｍｏｌ）から、Ｎ−（シクロブチルメチル）−３−［（４−｛［５−（フェニルスルホニル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボキサミド（７５ｍｇ、粗製アミドから２０％）：
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.７３−１.８１（ｍ，２Ｈ），１.８７−１.９９（ｍ，２Ｈ），２.０８−２.１５（ｍ，２Ｈ），２.５６−２.６５（ｍ，１Ｈ），３.４３−３.４６（ｍ，２Ｈ），６.３０（ｄ，１Ｈ），６.３７（ｂｒｓ，２Ｈ），７.１４−７.１７（ｍ，２Ｈ），７.３８（ｄ，１Ｈ），７.４１−７.４５（ｍ，１Ｈ），７.４５−７.４８（ｍ，２Ｈ），７.５５（ｄｄ，１Ｈ），７.６６−７.７２（ｍ，２Ｈ），８.０４−８.０６（ｍ，１Ｈ），８.３１（ｄｄ，１Ｈ），８.３６（ｓ，１Ｈ），８.４３−８.４７（ｍ，１Ｈ），８.５５−８.５８（ｍ，１Ｈ），９.３９（ｄｄ，１Ｈ），１２.８６（ｂｒｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５８１.０；及び、
Ｎ−（シクロブチルメチル）−３−［（４−｛［４−（フェニルスルホニル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボキサミド（３９ｍｇ、粗製アジドから１１％）：
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６９−１.７７（ｍ，２Ｈ），１.８４−１.９６（ｍ，２Ｈ），２.０５−２.１２（ｍ，２Ｈ），２.５２−２.６１（ｍ，１Ｈ），３.３９−３.４３（ｍ，２Ｈ），６.０２（ｓ，２Ｈ），７.４８−７.５４（ｍ，３Ｈ），７.５５−７.６３（ｍ，３Ｈ），７.８７−７.９２（ｍ，２Ｈ），８.０１−８.０４（ｍ，２Ｈ），８.２９（ｄｄ，１Ｈ），８.４１−８.４６（ｍ，１Ｈ），８.５７（ｄ，１Ｈ），９.３７（ｄｄ，１Ｈ），１２.９８（ｂｒｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺５８１.０；
を得た。 Examples 48 and 49
N- (cyclobutylmethyl) -3-[(4-{[5- (phenylsulfonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide and N- (cyclobutylmethyl) -3-[(4-{[4- (phenylsulfonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine- 2-carboxamide

Examples 15 and 16: 1-fluorovinylphenyl, obtained from the procedure of Matthews [Matthews; McCarthy; J. Org. Chem .; 1990, 55, 2973-2975] using a procedure similar to AB. Sulfone (235 mg, 1.26 mmol), and Examples 15 and 16: Crude methyl 3-{[4- (azidomethyl) -1-naphthoyl] amino} pyridine-2-carboxylate (228 mg, 0.8. 631 mmol) to N- (cyclobutylmethyl) -3-[(4-{[5- (phenylsulfonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] Pyridine-2-carboxamide (75 mg, 20% from crude amide):
¹ HNMR (500 MHz, CDCl ₃ ) δ (ppm): 1.73-1.81 (m, 2H), 1.87-1.99 (m, 2H), 2.08-2.15 (m, 2H) ), 2.56-2.65 (m, 1H), 3.43-3.46 (m, 2H), 6.30 (d, 1H), 6.37 (brs, 2H), 7.14- 7.17 (m, 2H), 7.38 (d, 1H), 7.41-7.45 (m, 1H), 7.45-7.48 (m, 2H), 7.55 (dd, 1H), 7.66-7.72 (m, 2H), 8.04-8.06 (m, 1H), 8.31 (dd, 1H), 8.36 (s, 1H), 8.43 −8.47 (m, 1H), 8.55-8.58 (m, 1H), 9.39 (dd, 1H), 12.86 (brs, 1H); MS (ESI): (M + H) ⁺ 581.0; and
N- (cyclobutylmethyl) -3-[(4-{[4- (phenylsulfonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide (39 mg, 11% from crude azide):
¹ HNMR (500 MHz, CDCl ₃ ) δ (ppm): 1.69-1.77 (m, 2H), 1.84-1.96 (m, 2H), 2.05-2.12 (m, 2H) ), 2.52-2.61 (m, 1H), 3.39-3.43 (m, 2H), 6.02 (s, 2H), 7.48-7.54 (m, 3H), 7.55-7.63 (m, 3H), 7.87-7.92 (m, 2H), 8.01-8.04 (m, 2H), 8.29 (dd, 1H), 8. 41-8.46 (m, 1H), 8.57 (d, 1H), 9.37 (dd, 1H), 12.98 (brs, 1H); MS (ESI): (M + H) ⁺ 581.0 ;
Got.

本化合物は、Ｎ−（シクロブチルメチル）−３−［（４−｛［５−（フェニルスルホニル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボキサミド及びＮ−（シクロブチルメチル）−３−［（４−｛［４−（フェニルスルホニル）−１Ｈ−１，２，３−トリアゾール−１−イル］メチル｝−１−ナフトイル）アミノ］ピリジン−２−カルボキサミドの合成（実施例４７及び４８を参照）からの副生成物（２ｍｇ、粗製アジドから０.７％ ）として単離された。
¹ＨＮＭＲ（５００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６４−１.７２（ｍ，２Ｈ），１.７９−１.９１（ｍ，２Ｈ），２.００−２.０８（ｍ，２Ｈ），２.４７−２.５６（ｍ，１Ｈ），３.３３−３.３７（ｍ，２Ｈ），５.９１（ｓ，２Ｈ），６.９９（ｄ，１Ｈ），７.４４（ｄ，１Ｈ），７.４７（ｄｄ，１Ｈ），７.５２−７.５８（ｍ，２Ｈ），７.８２（ｄ，１Ｈ），７.９２−７.９５（ｍ，１Ｈ），８.２４（ｄｄ，１Ｈ），８.３７−８.４２（ｍ，１Ｈ），８.４８−８.５１（ｍ，１Ｈ），９.３２（ｄｄ，１Ｈ），１２.８８（ｂｒｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺４５９.０。 Example 50
N- (cyclobutylmethyl) -3-({4-[(4-fluoro-1H-1,2,3-triazol-1-yl) methyl] -1-naphthoyl} amino) pyridine-2-carboxamide

This compound is N- (cyclobutylmethyl) -3-[(4-{[5- (phenylsulfonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] Pyridine-2-carboxamide and N- (cyclobutylmethyl) -3-[(4-{[4- (phenylsulfonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) Isolated as a by-product (2 mg, 0.7% from crude azide) from the synthesis of amino] pyridine-2-carboxamide (see Examples 47 and 48).
¹ HNMR (500 MHz, CDCl ₃ ) δ (ppm): 1.64-1.72 (m, 2H), 1.79-1.91 (m, 2H), 2.00-2.08 (m, 2H) ), 2.47-2.56 (m, 1H), 3.33-3.37 (m, 2H), 5.91 (s, 2H), 6.99 (d, 1H), 7.44 ( d, 1H), 7.47 (dd, 1H), 7.52-7.58 (m, 2H), 7.82 (d, 1H), 7.92-7.95 (m, 1H), 8 .24 (dd, 1H), 8.37-8.42 (m, 1H), 8.48-8.51 (m, 1H), 9.32 (dd, 1H), 12.88 (brs, 1H) ); MS (ESI): (M + H) ⁺ 459.0.

Example 51
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1-methyl-1H-indole-3-carboxamide

標題の化合物を、実施例５１Ｂから得た３−アミノ−Ｎ−（シクロブチルメチル）ピリジン−２−カルボキサミドに、一般的手順３を適用して製造した。１Ｈ−インドール−３−カルボン酸クロリドを、一般的手順２に従って生成した。反応混合物に水性処理（ＮａＨＣＯ₃）を行い、有機層を分離し、乾燥した。M粗製の生成物を、ＥｔＯＡｃ／ヘプタン（１／２）の溶離液を用いたシリカゲルベースのクロマトグラフィーで精製し、標題の化合物（９３％）を無色の固体として得た。
¹ＨＮＭＲ（ＣＤＣｌ₃，４００ＭＨｚ）δ（ｐｐｍ）：１.７５−１.８６（ｍ，２Ｈ），１.８９−２.００（ｍ，２Ｈ），２.１０−２.１９（ｍ，２Ｈ），２.５７−２.７０（ｍ，１Ｈ），３.４７−３.５３（ｍ，２Ｈ），３.８６（ｓ，１Ｈ），７.２８−７.３６（ｍ，４Ｈ），７.４２（ｄ，１Ｈ），７.８３（ｓ，３Ｈ），８.１７（ｄｄ，１Ｈ），８.４１−８.５０（ｍ，２Ｈ），９.３１（ｄｄ，１Ｈ），１２.７１（ｂｓ，１Ｈ）。 Example 51A
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1-methyl-1H-indole-3-carboxamide

The title compound was prepared by applying General Procedure 3 to 3-amino-N- (cyclobutylmethyl) pyridine-2-carboxamide obtained from Example 51B. 1H-indole-3-carboxylic acid chloride was produced according to General Procedure 2. The reaction mixture was subjected to aqueous treatment (NaHCO ₃ ) and the organic layer was separated and dried. The crude M product was purified by silica gel based chromatography using an EtOAc / heptane (1/2) eluent to give the title compound (93%) as a colorless solid.
¹ HNMR (CDCl ₃ , 400 MHz) δ (ppm): 1.75-1.86 (m, 2H), 1.89-2.00 (m, 2H), 2.10-2.19 (m, 2H) ), 2.57-2.70 (m, 1H), 3.47-3.53 (m, 2H), 3.86 (s, 1H), 7.28-7.36 (m, 4H), 7.42 (d, 1H), 7.83 (s, 3H), 8.17 (dd, 1H), 8.41-8.50 (m, 2H), 9.31 (dd, 1H), 12 .71 (bs, 1H).

標題の化合物を、３−アミノピリジン−２−カルボン酸に一般的手順５を適用して製造した。反応混合物に水性処理（ＮａＨＣＯ₃）を行い、有機層を分離し、乾燥した。粗製の生成物を、ＥｔＯＡｃ／ヘプタン＝１／１の溶離液を用いたシリカゲルベースのクロマトグラフィーで精製し、標題の化合物（２８％）を得た。
¹ＨＮＭＲ（ＣＤＣｌ₃，４００ＭＨｚ）δ（ｐｐｍ）：１.７１（ｍ，２Ｈ），１.８６−１.９６（ｍ，２Ｈ），２.０６−２.１５（ｍ，２Ｈ），２.５３−２.６５（ｍ，１Ｈ），３.４１−３.４６（ｍ，２Ｈ），５.９５（ｂｓ，２Ｈ），６.９８（ｄ，１Ｈ），７.１４（ｄｄ，１Ｈ），７.８５（ｄ，１Ｈ），８.０９（ｂｓ，１Ｈ）。 Example 51B
3-Amino-N- (cyclobutylmethyl) pyridine-2-carboxamide

The title compound was prepared by applying general procedure 5 to 3-aminopyridine-2-carboxylic acid. The reaction mixture was subjected to aqueous treatment (NaHCO ₃ ) and the organic layer was separated and dried. The crude product was purified by silica gel based chromatography using an eluent of EtOAc / heptane = 1/1 to give the title compound (28%).
¹ HNMR (CDCl ₃ , 400 MHz) δ (ppm): 1.71 (m, 2H), 1.86-1.96 (m, 2H), 2.06-2.15 (m, 2H), 2. 53-2.65 (m, 1H), 3.41-3.46 (m, 2H), 5.95 (bs, 2H), 6.98 (d, 1H), 7.14 (dd, 1H) , 7.85 (d, 1H), 8.09 (bs, 1H).

標題の化合物を、３−アミノ−Ｎ−（シクロブチルメチル）ピリジン−２−カルボキサミドに対して一般的手順３を適用することにより製造した。酸クロリドは、１−メチル−１Ｈ−インドール−２−カルボン酸から出発して、一般的手順２に従って製造した。反応溶液に水性処理（ＮａＨＣＯ₃）を行い、シリカゲルベースのクロマトグラフィー（ＥｔＯＡｃ／ヘプタン＝１／２）で精製し、標題の化合物（３９％）を無色の固体として得た。
¹ＨＮＭＲ（ＣＤＣｌ₃，４００ＭＨｚ）δ（ｐｐｍ）：１.７４−１.８７（ｍ，２Ｈ），１.８９−１.９９（ｍ，２Ｈ），２.１０−２.２０（ｍ，２Ｈ），２.５８−２.７２（ｍ，１Ｈ），４.１３（ｓ，３Ｈ），７.１４−７.１９（ｍ，１Ｈ），７.３２−７.４７（ｍ，４Ｈ），７.７４（ｄ，１Ｈ），８.２３（ｄｄ，１Ｈ），８.４７（ｂｓ，１Ｈ），９.２３（ｄｄ，１Ｈ），１３.１５（ｂｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺３６３.１；ＭＳ（ＥＳＩ）（Ｍ−Ｈ）^-３６１.０。 Example 52
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1-methyl-1H-indole-2-carboxamide

The title compound was prepared by applying general procedure 3 to 3-amino-N- (cyclobutylmethyl) pyridine-2-carboxamide. The acid chloride was prepared according to General Procedure 2, starting from 1-methyl-1H-indole-2-carboxylic acid. The reaction solution was treated with aqueous (NaHCO ₃ ) and purified by silica gel based chromatography (EtOAc / heptane = 1/2) to give the title compound (39%) as a colorless solid.
¹ HNMR (CDCl ₃ , 400 MHz) δ (ppm): 1.74-1.87 (m, 2H), 1.89-1.99 (m, 2H), 2.10-2.20 (m, 2H) ), 2.58-2.72 (m, 1H), 4.13 (s, 3H), 7.14-7.19 (m, 1H), 7.32-7.47 (m, 4H), 7.74 (d, 1H), 8.23 (dd, 1H), 8.47 (bs, 1H), 9.23 (dd, 1H), 13.15 (bs, 1H); MS (ESI): (M + H) ^<+ >363.1; MS (ESI) (M-H) < ^- > 361.0.

標題の化合物を、３−アミノ−Ｎ−（シクロブチルメチル）ピリジン−２−カルボキサミドに対して一般的手順３を適用して製造した。酸クロリドは、１Ｈ−インドール−３−カルボン酸と、それに続く一般的手順２から製造した。精製は、逆相ＨＰＬＣ（ＣＨ₃ＣＮ／水、緩衝液としてＣＨ₃ＣＯＯＨ）を操作して行われた。標題の化合物を含む画分は減圧下で蒸発させ、そして残留した水相をＮａＨＣＯ₃（固体）で塩基性にし、ＣＨ₂Ｃｌ₂で抽出した。有機相を乾燥し、濃縮して、標題の化合物（２３％）を無色の固体として得た。
¹ＨＮＭＲ（ＣＤＣｌ₃，４００ＭＨｚ）δ（ｐｐｍ）：１.７４−１.８５（ｍ，２Ｈ），１.８８−１.９８（ｍ，２Ｈ），２.０９−２.１９（ｍ，２Ｈ），２.５７−２.６９（ｍ，１Ｈ），３.４８−３.５２（ｍ，２Ｈ），７.２７−７.３３（ｍ，２Ｈ），７.４０−７.４７（ｍ，２Ｈ），８.００（ｄ，１Ｈ），８.１９（ｄｄ，１Ｈ），８.４１−８.４５（ｍ，１Ｈ），８.５０（ｂｓ，１Ｈ），８.７８（ｂｓ，１Ｈ），９.３２（ｄｄ，１Ｈ），１２.８２（ｂｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺３４９.１；ＭＳ（ＥＳＩ）（Ｍ−Ｈ）^-３４７.０。 Example 53
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1H-indole-3-carboxamide

The title compound was prepared by applying General Procedure 3 to 3-amino-N- (cyclobutylmethyl) pyridine-2-carboxamide. The acid chloride was prepared from 1H-indole-3-carboxylic acid followed by general procedure 2. Purification was performed by operating reverse phase HPLC (CH ₃ CN / water, CH ₃ COOH as buffer). Fractions containing the title compound were evaporated under reduced pressure and the remaining aqueous phase was basified with NaHCO ₃ (solid) and extracted with CH ₂ Cl ₂ . The organic phase was dried and concentrated to give the title compound (23%) as a colorless solid.
¹ HNMR (CDCl ₃ , 400 MHz) δ (ppm): 1.74-1.85 (m, 2H), 1.88-1.98 (m, 2H), 2.09-2.19 (m, 2H) ), 2.57-2.69 (m, 1H), 3.48-3.52 (m, 2H), 7.27-7.33 (m, 2H), 7.40-7.47 (m , 2H), 8.00 (d, 1H), 8.19 (dd, 1H), 8.41-8.45 (m, 1H), 8.50 (bs, 1H), 8.78 (bs, 1H), 9.32 (dd, 1H), 12.82 (bs, 1H); MS (ESI): (M + H) ⁺ 349.1; MS (ESI) (M−H) ⁻ 347.0.

Example 54
N- {2-[(cyclobutylmethyl) carbamoyl] -4-methoxyphenyl} quinoline-4-carboxamide

標題の化合物を、実施例５４Ｂから得た５−メトキシ−２−［（キノリン−４−イルカルボニル）アミノ］安息香酸メチルに対して、一般的手順４を適用し、そしてシクロブチルメチルアミンを用いて製造した。反応混合物を直接、ＥｔＯＡｃ／ヘプタン（１／４→１／１）を溶離液として用いる、シリカゲルベースのクロマトグラフィーで精製し、標題の化合物（８０％）を無色の固体として得た。
¹ＨＮＭＲ（ＣＤＣｌ₃，４００ＭＨｚ）δ（ｐｐｍ）：１.６９−１.８１（ｍ，２Ｈ），１.８５−１.９８（ｍ，２Ｈ），２.０５−２.１５（ｍ，２Ｈ），２.５２−２.６５（ｍ，１Ｈ），３.３９−３.４５（ｍ，２Ｈ），３.９５（ｓ，３Ｈ），７.０３（ｄ，１Ｈ），７.５９−７.６５（ｍ，１Ｈ），７.７１（ｄ，１Ｈ），７.７４−７.８０（ｍ，１Ｈ），８.１２−８.２０（ｍ，２Ｈ），８.４７（ｄ，１Ｈ），９.０４（ｄ，１Ｈ），９.３０（ｄ，１Ｈ），１２.８２（ｂｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺３９１.２；ＭＳ（ＥＳＩ）（Ｍ−Ｈ）^-３８９.１。 Example 54A
N- {2-[(cyclobutylmethyl) carbamoyl] -4-methoxyphenyl} quinoline-4-carboxamide

Apply the general procedure 4 to the title compound to methyl 5-methoxy-2-[(quinolin-4-ylcarbonyl) amino] benzoate from Example 54B and use cyclobutylmethylamine. Manufactured. The reaction mixture was directly purified by silica gel based chromatography using EtOAc / heptane (1/4 → 1/1) as eluent to give the title compound (80%) as a colorless solid.
¹ HNMR (CDCl ₃ , 400 MHz) δ (ppm): 1.69-1.81 (m, 2H), 1.85-1.98 (m, 2H), 2.05-2.15 (m, 2H) ), 2.52-2.65 (m, 1H), 3.39-3.45 (m, 2H), 3.95 (s, 3H), 7.03 (d, 1H), 7.59- 7.65 (m, 1H), 7.71 (d, 1H), 7.74-7.80 (m, 1H), 8.12-8.20 (m, 2H), 8.47 (d, 1H), 9.04 (d, 1H), 9.30 (d, 1H), 12.82 (bs, 1H); MS (ESI): (M + H) ⁺ 391.2; MS (ESI) (M− ^H) - 389.1.

標題の化合物を、実施例１Ｅからの３−アミノ−６−メトキシピリジン−２−カルボン酸に一般的手順６ｂを適用することにより得られた３−アミノ−６−メトキシピリジン−２−カルボン酸メチルに対して一般的手順３を適用することにより製造した。酸クロリドを、キノリン−４−カルボン酸に一般的手順２を適用することにより製造した。反応混合物に水性処理（ＮａＨＣＯ₃）を行い、有機相を分離し、乾燥した。粗製の生成物を、ＣＨ₂Ｃｌ₂／ＥｔＯＡｃ（１／０→４／１）を溶離液として用いる、シリカゲルベースのクロマトグラフィーで精製し、標題の化合物（３９％）を無色の固体として得た。
¹ＨＮＭＲ（ＣＤＣｌ₃，４００ＭＨｚ）δ（ｐｐｍ）：３.９６（ｓ，３Ｈ），４.０１（ｓ，３Ｈ），７.１０（ｄ，１Ｈ），７.６５（ｄｄｄ，１Ｈ），７.６９（ｄ，１Ｈ），７.８０（ｄｄｄ，１Ｈ），８.２０（ｄ，１Ｈ），８.４５（ｄ，１Ｈ），９.０７（ｄ，１Ｈ），９.２５（ｄ，１Ｈ），１１.５５（ｂｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺３３８.１。 Example 54B
Methyl 5-methoxy-2-[(quinolin-4-ylcarbonyl) amino] benzoate

The methyl 3-amino-6-methoxypyridine-2-carboxylate obtained by applying general procedure 6b to the 3-amino-6-methoxypyridine-2-carboxylic acid from Example 1E Was prepared by applying General Procedure 3. The acid chloride was prepared by applying general procedure 2 to quinoline-4-carboxylic acid. The reaction mixture was subjected to aqueous treatment (NaHCO ₃ ) and the organic phase was separated and dried. The crude product was purified by silica gel based chromatography using CH ₂ Cl ₂ / EtOAc (1/0 → 4/1) as eluent to give the title compound (39%) as a colorless solid. .
¹ HNMR (CDCl ₃ , 400 MHz) δ (ppm): 3.96 (s, 3H), 4.01 (s, 3H), 7.10 (d, 1H), 7.65 (ddd, 1H), 7 .69 (d, 1H), 7.80 (ddd, 1H), 8.20 (d, 1H), 8.45 (d, 1H), 9.07 (d, 1H), 9.25 (d, 1H), 11.55 (bs, 1H); MS (ESI): (M + H) ⁺ 338.1.

Example 55
N- {2-[(cyclobutylmethyl) carbamoyl] -6-methoxypyridin-3-yl} -1-methyl-1H-indazole-3-carboxamide

標題の化合物を、６−メトキシ−３−｛［（１−メチル−１Ｈ−インダゾール−３−イル）カルボニル］アミノ｝ピリジン−２−カルボン酸メチル（実施例５５Ｂから得た）に対して一般的手順４を適用し、そしてシクロブチルメチルアミンを用いることにより製造した。９０℃で６時間加熱した後、再度反応混合物をマイクロウエーブ照射を用いて１５０℃で３０分間加熱した。シリカゲルベースでのクロマトグラフィーによる精製を、ＥｔＯＡｃ／ヘプタン（２／３）の無勾配系で行い、標題の化合物（１２％）を無色の固体として得た。
¹ＨＮＭＲ（ＣＤＣｌ₃，４００ＭＨｚ）δ（ｐｐｍ）：１.７５−１.８６（ｍ，２Ｈ），１.９０−２.０１（ｍ，２Ｈ），２.０９−２.１９（ｍ，２Ｈ），２.５９−２.７０（ｍ，１Ｈ），３.５１−３.５７（ｍ，２Ｈ），３.９４（ｓ，３Ｈ），４.２２（ｓ，３Ｈ），６.９７（ｄ，１Ｈ），７.２９−７.３４（ｍ，１Ｈ），７.４３−７.４６（ｍ，２Ｈ），８.１６（ｂｓ，１Ｈ），８.４１（ｄ，１Ｈ），９.３２（ｄ，１Ｈ），１３.０７（ｂｓ，１Ｈ）；ＭＳ（ＥＳＩ）（Ｍ＋Ｈ）⁺３９４.２；ＭＳ（ＥＳＩ）：（Ｍ−Ｈ）^-３９２.１。 Example 55A
N- {2-[(cyclobutylmethyl) carbamoyl] -6-methoxypyridin-3-yl} -1-methyl-1H-indazole-3-carboxamide

The title compound is generic to methyl 6-methoxy-3-{[(1-methyl-1H-indazol-3-yl) carbonyl] amino} pyridine-2-carboxylate (obtained from Example 55B). Prepared by applying procedure 4 and using cyclobutylmethylamine. After heating at 90 ° C. for 6 hours, the reaction mixture was again heated at 150 ° C. for 30 minutes using microwave irradiation. Silica gel-based chromatographic purification was performed on an EtOAc / heptane (2/3) gradient system to give the title compound (12%) as a colorless solid.
¹ HNMR (CDCl ₃ , 400 MHz) δ (ppm): 1.75-1.86 (m, 2H), 1.90-2.01 (m, 2H), 2.09-2.19 (m, 2H) ), 2.59-2.70 (m, 1H), 3.51-3.57 (m, 2H), 3.94 (s, 3H), 4.22 (s, 3H), 6.97 ( d, 1H), 7.29-7.34 (m, 1H), 7.43-7.46 (m, 2H), 8.16 (bs, 1H), 8.41 (d, 1H), 9 .32 (d, 1 H), 13.07 (bs, 1 H); MS (ESI) (M + H) ⁺ 394.2; MS (ESI): (M−H) ⁻ 392.1.

標題の化合物を、実施例１Ｅからの３−アミノ−６−メトキシ−ピリジン−２−カルボン酸に対して、一般的手順６ｂを適用することにより得た、３−アミノ−６−メトキシピリジン−２−カルボン酸メチルに対して一般的手順３を適用することにより製造した。酸クロリドは、１−メチル−１Ｈ−インダゾール−３−カルボン酸に対して、一般的手順２を適用することにより製造した。反応溶液を水性処理（ＮａＨＣＯ₃）し、精製をシリカゲルベースでのクロマトグラフィー（ＣＨ₂Ｃｌ₂／ＥｔＯＡｃ＝１／０→４／１）を用いて行い、標題の化合物（６７％）を無色の固体として得た。
¹ＨＮＭＲ（ＣＤＣｌ₃，４００ＭＨｚ）δ（ｐｐｍ）：３.９９（ｓ，３Ｈ），４.０６（ｓ，３Ｈ），４.２２（ｓ，３Ｈ），７.０４（ｄ，１Ｈ），７.３１−７.３６（ｍ，１Ｈ），７.４５−７.４８（ｍ，２Ｈ），８.４１（ｄ，１Ｈ），９.２７（ｄ，１Ｈ），１２.０６（ｂｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺３４１.１。 Example 55B
Methyl 6-methoxy-3-{[(1-methyl-1H-indazol-3-yl) carbonyl] amino} pyridine-2-carboxylate

The title compound was obtained by applying general procedure 6b to 3-amino-6-methoxy-pyridine-2-carboxylic acid from Example 1E. Prepared by applying general procedure 3 to methyl carboxylate. The acid chloride was prepared by applying general procedure 2 to 1-methyl-1H-indazole-3-carboxylic acid. The reaction solution is treated aqueous (NaHCO ₃ ) and purification is performed using silica gel based chromatography (CH ₂ Cl ₂ / EtOAc = 1/0 → 4/1) to give the title compound (67%) as a colorless compound. Obtained as a solid.
¹ HNMR (CDCl ₃ , 400 MHz) δ (ppm): 3.99 (s, 3H), 4.06 (s, 3H), 4.22 (s, 3H), 7.04 (d, 1H), 7 .31-7.36 (m, 1H), 7.45-7.48 (m, 2H), 8.41 (d, 1H), 9.27 (d, 1H), 12.06 (bs, 1H) ); MS (ESI): (M + H) ⁺ 341.1.

Example 56
3-[(1-Benzothien-3-yl-carbonyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

一般的手順６に従い、ベンゾチオフェン−３−カルボン酸クロリド（ベンゾチオフェン−３−カルボン酸（１７８ｍｇ、１ｍｍｏｌ）から一般的手順２を用いて製造した）、及び実施例５６Ｂから得た３−アミノ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（７４ｍｇ、０.３ｍｍｏｌ）を用い、精製後、標題の化合物（１０２ｍｇ、収率８６％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：１.２７−１.４１（ｍ，２Ｈ），１.６７（ｂｄ，２Ｈ），１.８６−１.９８（ｍ，１Ｈ），３.３１（ｄ，２Ｈ），３.３８（ｄｄ，２Ｈ），３.９３（ｄｄ，２Ｈ），７.３９−７.５０（ｍ，２Ｈ），７.５５（ｄｄ，１Ｈ），７.９５（ｄ，１Ｈ），８.３１（ｄｄ，１Ｈ），８.４０（ｓ，１Ｈ），８.５８（ｄ，１Ｈ），９.１８（ｄｄ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺：３９６。 Example 56A
3-[(1-Benzothien-3-ylcarbonyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

According to general procedure 6, benzothiophene-3-carboxylic acid chloride (prepared using general procedure 2 from benzothiophene-3-carboxylic acid (178 mg, 1 mmol)) and 3-amino-obtained from example 56B After purification using N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (74 mg, 0.3 mmol), the title compound (102 mg, 86% yield) was obtained.
¹ HNMR (400 MHz, CD ₃ OD) δ (ppm): 1.27-1.41 (m, 2H), 1.67 (bd, 2H), 1.86-1.98 (m, 1H), 3 .31 (d, 2H), 3.38 (dd, 2H), 3.93 (dd, 2H), 7.39-7.50 (m, 2H), 7.55 (dd, 1H), 7. 95 (d, 1H), 8.31 (dd, 1H), 8.40 (s, 1H), 8.58 (d, 1H), 9.18 (dd, 1H); MS (ESI): (M + H ) ⁺ : 396.

一般的手順５に従い、３−アミノピリジン−２−カルボン酸（６.７ｇ、４８.６ｍｍｏｌ）及び１−（４−テトラヒドロピラニル）−メチルアミン（５.６ｇ、４８.６ｍｍｏｌ）を用い、ヘキサンからの再結晶後、標題の化合物（７.４ｇ、収率６５％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.２９−１.４２（ｍ，２Ｈ），１.６５（ｂｄ，２Ｈ），１.７５−１.８９（ｍ，１Ｈ），３.２８（ｔ，２Ｈ），３.３４（ｄｄ，２Ｈ），３.９５（ｄｄ，２Ｈ），５.９４（ｂｓ，２Ｈ），６.９６（ｄ，１Ｈ），７.１１（ｄｄ，１Ｈ），７.８０（ｄ，１Ｈ），８.２０（ｂｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺：２３６。 Example 56B
3-Amino-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

According to general procedure 5, using 3-aminopyridine-2-carboxylic acid (6.7 g, 48.6 mmol) and 1- (4-tetrahydropyranyl) -methylamine (5.6 g, 48.6 mmol) in hexane After recrystallization from the title compound (7.4 g, 65% yield) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.29-1.42 (m, 2H), 1.65 (bd, 2H), 1.75-1.89 (m, 1H), 3. 28 (t, 2H), 3.34 (dd, 2H), 3.95 (dd, 2H), 5.94 (bs, 2H), 6.96 (d, 1H), 7.11 (dd, 1H) ), 7.80 (d, 1H), 8.20 (bs, 1H); MS (ESI): (M + H) ⁺ : 236.

一般的手順６に従い、５，６，７，８−テトラヒドロナフタレン−１−カルボン酸クロリド（５，６，７，８−テトラヒドロナフタレン−１−カルボン酸（１７６ｍｇ、１ｍｍｏｌ）から一般的手順２を用いて製造した）、及び実施例５６Ｂから得た３−アミノ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（７４ｍｇ、０.３ｍｍｏｌ）を用い、精製後、標題の化合物（５７ｍｇ、収率４８.５％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：１.２１−１.３４（ｍ，２Ｈ），１.６０（ｂｄ，２Ｈ），１.７７−１.８８（ｍ，１Ｈ 水ピークの後に、部分的に隠れている），２.７２−２.８３（ｍ，４Ｈ），２.９０（ｂｔ，２Ｈ），３.００（ｂｔ，２Ｈ），３.２１（ｄ，２Ｈ），３.３２（ｄｄ，２Ｈ），３.８８（ｄｄ，２Ｈ），７.０７（ｔ，１Ｈ），７.１３−７.２０（ｍ，２Ｈ），７.３１−７.３６（ｍ，１Ｈ），７.５０（ｄｄ，１Ｈ），７.５９（ｄ，１Ｈ），８.２７（ｄ，１Ｈ），９.１２（ｄ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺：３９４。 Example 57
3-[(5,6,7,8-tetrahydronaphthalen-1-ylcarbonyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

According to general procedure 6, using general procedure 2 from 5,6,7,8-tetrahydronaphthalene-1-carboxylic acid chloride (5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (176 mg, 1 mmol) And the title compound after purification using 3-amino-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (74 mg, 0.3 mmol) from Example 56B. (57 mg, 48.5% yield) was obtained.
¹ HNMR (400 MHz, CD ₃ OD) δ (ppm): 1.21-1.34 (m, 2H), 1.60 (bd, 2H), 1.77-1.88 (m, 1H of water peak Later, partially hidden), 2.72-2.83 (m, 4H), 2.90 (bt, 2H), 3.00 (bt, 2H), 3.21 (d, 2H), 3.32 (dd, 2H), 3.88 (dd, 2H), 7.07 (t, 1H), 7.13-7.20 (m, 2H), 7.31-7.36 (m, 1H), 7.50 (dd, 1H), 7.59 (d, 1H), 8.27 (d, 1H), 9.12 (d, 1H); MS (ESI): (M + H) ⁺ : 394 .

一般的手順６に従い、１Ｈ−インダゾール−３−カルボン酸クロリド（１Ｈ−インダゾール−３−カルボン酸（１６２ｍｇ、１ｍｍｏｌ）から一般的手順２を用いて製造した）及び実施例５６Ｂから得た３−アミノ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（７４ｍｇ、０.３ｍｍｏｌ）を用い、精製後、標題の化合物（７ｍｇ、収率：６.２％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：１.２９−１.４２（ｍ，２Ｈ），１.６９（ｂｄ，２Ｈ），１.８６−２.０１（ｍ，１Ｈ），３.３３（ｄ，２Ｈ），３.３９（ｄｄ，２Ｈ），３.９３（ｄｄ，２Ｈ），７.２８（ｔ，１Ｈ），７.４３（ｔ，１Ｈ），７.５５（ｄｄ，１Ｈ），８.２５−８.３３（ｓ＋ｔ，２Ｈ），９.２９（ｄ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺：３８０。 Example 58
N- {2-[(Tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1H-indazole-3-carboxamide

According to general procedure 6, 1H-indazole-3-carboxylic acid chloride (prepared using general procedure 2 from 1H-indazole-3-carboxylic acid (162 mg, 1 mmol)) and the 3-amino obtained from Example 56B After purification using -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (74 mg, 0.3 mmol), the title compound (7 mg, yield: 6.2%) was obtained.
¹ HNMR (400 MHz, CD ₃ OD) δ (ppm): 1.29-1.42 (m, 2H), 1.69 (bd, 2H), 1.86-2.01 (m, 1H), 3 .33 (d, 2H), 3.39 (dd, 2H), 3.93 (dd, 2H), 7.28 (t, 1H), 7.43 (t, 1H), 7.55 (dd, 1H), 8.25-8.33 (s + t, 2H), 9.29 (d, 1H); MS (ESI): (M + H) ⁺ : 380.

一般的手順６に従い、１Ｈ−インドール−３−カルボン酸クロリド（１Ｈ−インドール−３−カルボン酸（１６１ｍｇ、１ｍｍｏｌ）から一般的手順２を用いて製造した）及び実施例５６Ｂから得た３−アミノ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（７４ｍｇ、０.３ｍｍｏｌ）を用い、精製後、標題の化合物（８９ｍｇ、収率：７８.５％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：１.３４−１.４８（ｍ，２Ｈ），１.７０（ｄ，２Ｈ），１.８３−１.９６（ｍ，１Ｈ），３.３３−３.４４（ｄ＋ｄｄ，４Ｈ），３.９９（ｄｄ，２Ｈ），７.２８（ｔ，２Ｈ），７.３７−７.４９（ｍ，２Ｈ），７.９９（ｓ，１Ｈ），８.１７（ｄ，１Ｈ），８.４０（ｄ，１Ｈ），８.５９−８.７１（２ｓ，２Ｈ），９.３２（ｄ，１Ｈ），１２.７４（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺：３７９。 Example 59
N- {2-[(Tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1H-indole-3-carboxamide

According to general procedure 6, 1H-indole-3-carboxylic acid chloride (prepared using general procedure 2 from 1H-indole-3-carboxylic acid (161 mg, 1 mmol)) and 3-amino obtained from Example 56B After purification using -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (74 mg, 0.3 mmol), the title compound (89 mg, yield: 78.5%) was obtained.
¹ HNMR (400 MHz, CD ₃ OD) δ (ppm): 1.34-1.48 (m, 2H), 1.70 (d, 2H), 1.83-1.96 (m, 1H), 3 .33-3.44 (d + dd, 4H), 3.99 (dd, 2H), 7.28 (t, 2H), 7.37-7.49 (m, 2H), 7.99 (s, 1H) ), 8.17 (d, 1H), 8.40 (d, 1H), 8.59-8.71 (2s, 2H), 9.32 (d, 1H), 12.74 (s, 1H) MS (ESI): (M + H) ^<+> : 379.

一般的手順６に従い、Ｎ−メチル−インドール−３−カルボン酸クロリド（Ｎ−メチル−インドール−３−カルボン酸（１７５ｍｇ、１ｍｍｏｌ）から一般的手順２を用いて製造した）及び実施例５６Ｂから得た３−アミノ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（１２５ｍｇ、０.５ｍｍｏｌ）を用い、精製後、標題の化合物（１２１ｍｇ、収率：６２％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）１.３０−１.４３（ｍ，２Ｈ），１.６９（ｂｄ，２Ｈ），１.８５−１.９８（ｍ，１Ｈ），３.３３（ｄ，２Ｈ），３.３９（ｄｄ，２Ｈ），３.８９（ｓ，３Ｈ），３.９４（ｄｄ，２Ｈ），７.１９−７.３１（２ｔ，２Ｈ），７.４３（ｄ，１Ｈ），７.４７（ｄｄ，１Ｈ），７.９２（ｓ，１Ｈ），８.２０−８.２８（ｓ＋ｄ，２Ｈ），９.１４（ｄ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺３９３。 Example 60
1-methyl-N- {2-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1H-indole-3-carboxamide

Obtained from N-methyl-indole-3-carboxylic acid chloride (prepared using general procedure 2 from N-methyl-indole-3-carboxylic acid (175 mg, 1 mmol)) according to general procedure 6 and Example 56B. The title compound (121 mg, yield: 62%) was obtained after purification using 3-amino-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (125 mg, 0.5 mmol). It was.
¹ HNMR (400 MHz, CD ₃ OD) δ (ppm) 1.30-1.43 (m, 2H), 1.69 (bd, 2H), 1.85-1.98 (m, 1H), 3. 33 (d, 2H), 3.39 (dd, 2H), 3.89 (s, 3H), 3.94 (dd, 2H), 7.19-7.31 (2t, 2H), 7.43 (D, 1H), 7.47 (dd, 1H), 7.92 (s, 1H), 8.20-8.28 (s + d, 2H), 9.14 (d, 1H); MS (ESI) : (M + H) ⁺ 393.

一般的手順６に従い、１，３−ベンゾチアゾール−６−カルボン酸クロリド（１，３−ベンゾチアゾール−６−カルボン酸（１７９ｍｇ、１ｍｍｏｌ）から一般的手順２を用いて製造した）、及び実施例５６Ｂから得た３−アミノ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（７４ｍｇ、０.３ｍｍｏｌ）を用い、精製後、標題の化合物（１５.４ｍｇ、収率：１２.９％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.３５−１.４９（ｍ，２Ｈ），１.７１（ｂｄ，２Ｈ），１.８４−１.９８（ｍ，１Ｈ），３.３４−３.４４（ｍ，４Ｈ），３.９９（ｄｄ，２Ｈ），７.５０（ｄｄ，１Ｈ），８.１７−８.２８（ｍ，３Ｈ），８.６７（ｂｔ，１Ｈ），８.７１（ｓ，１Ｈ），９.１４（ｓ，１Ｈ），９.３４（ｄ，１Ｈ），１３.３０（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺：３９７。 Example 61
N- {2-[(Tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1,3-benzothiazole-6-carboxamide

According to general procedure 6, 1,3-benzothiazole-6-carboxylic acid chloride (prepared using general procedure 2 from 1,3-benzothiazole-6-carboxylic acid (179 mg, 1 mmol)) and examples After purification using 3-amino-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (74 mg, 0.3 mmol) obtained from 56B, the title compound (15.4 mg, yield: 12.9%).
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.35-1.49 (m, 2H), 1.71 (bd, 2H), 1.84-1.98 (m, 1H), 3. 34-3.44 (m, 4H), 3.99 (dd, 2H), 7.50 (dd, 1H), 8.17-8.28 (m, 3H), 8.67 (bt, 1H) , 8.71 (s, 1H), 9.14 (s, 1H), 9.34 (d, 1H), 13.30 (s, 1H); MS (ESI): (M + H) ⁺ : 397.

一般的手順６に従い、１，６−ナフトピリジン−５−カルボン酸クロリド（１，６−ナフトピリジン−５−カルボン酸（１７４ｍｇ、１ｍｍｏｌ）から一般的手順２を用いて製造した）、及び実施例５６Ｂから得た３−アミノ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（１２５ｍｇ、０.５ ｍｍｏｌ）を用い、精製後、標題の化合物（５７ｍｇ、収率：２９％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：１.３０−１.４３（ｍ，２Ｈ），１.７０（ｂｄ，２Ｈ），１.８６−１.９９（ｍ，１Ｈ），３.３１−３.４４（２ｔ，４Ｈ），３.９３（ｂｄｄ，２Ｈ），７.５５（ｄｄ，１Ｈ），７.７１（ｄｄ，１Ｈ），８.０９（ｄ，１Ｈ），８.３２（ｄ，１Ｈ），８.９１（ｄ，１Ｈ），９.０５−９.１４（ｍ，２Ｈ），９.３２（ｄ，１Ｈ），９.８９（ｄ，１Ｈ），１３.８８（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺：３９２。 Example 62
N- {2-[(Tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1,6-naphthyridine-5-carboxamide

According to general procedure 6, 1,6-naphthopyridine-5-carboxylic acid chloride (prepared using general procedure 2 from 1,6-naphthopyridine-5-carboxylic acid (174 mg, 1 mmol)) and examples After purification using 3-amino-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (125 mg, 0.5 mmol) obtained from 56B, the title compound (57 mg, yield: 29 %).
¹ HNMR (400 MHz, CD ₃ OD) δ (ppm): 1.30 to 1.43 (m, 2H), 1.70 (bd, 2H), 1.86 to 1.99 (m, 1H), 3 .31-3.44 (2t, 4H), 3.93 (bdd, 2H), 7.55 (dd, 1H), 7.71 (dd, 1H), 8.09 (d, 1H), 8. 32 (d, 1H), 8.91 (d, 1H), 9.05-9.14 (m, 2H), 9.32 (d, 1H), 9.89 (d, 1H), 13.88 (S, 1 H); MS (ESI): (M + H) ⁺ : 392.

一般的手順６ｂに従い、６−フルオロ−４Ｈ−１，３−ベンゾジオキシン−８−カルボン酸クロリド（６−フルオロ−４Ｈ−１，３−ベンゾジオキシン−８−カルボン酸（９９ｍｇ、０.５ｍｍｏｌ）から、一般的手順２を用いて製造した）、及び実施例５６Ｂから得た３−アミノ−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（１１８ｍｇ、０.５ｍｍｏｌ）を用い、精製後、標題の化合物（１４３ｍｇ、収率：６９％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤ₃ＯＤ）δ（ｐｐｍ）：１.２７−１.４０（ｍ，２Ｈ），１.６２−１.７１（ｂｄ，２Ｈ），１.８２−１.９４（ｍ，１Ｈ），３.２８−３.３２（ｄ，２Ｈ；部分的に溶媒に隠れている），３.３８（ｄｔ，２Ｈ），３.８８−３.９６（ｂｄ，２Ｈ），４.９７（ｓ，２Ｈ），５.４６（ｓ，２Ｈ），７.０５（ｄｄ，１Ｈ），７.５１（ｄｄ，１Ｈ），７.５７（ｄｄ，１Ｈ），８.３１（ｄ，１Ｈ），９.２０（ｄ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺：４１６。 Example 63
3-{[(6-Fluoro-4H-1,3-benzodioxin-8-yl) carbonyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

According to general procedure 6b from 6-fluoro-4H-1,3-benzodioxin-8-carboxylic acid chloride (6-fluoro-4H-1,3-benzodioxin-8-carboxylic acid (99 mg, 0.5 mmol) And 3-amino-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide (118 mg, 0.5 mmol) obtained from Example 56B. After purification, the title compound (143 mg, yield: 69%) was obtained.
¹ HNMR (400 MHz, CD ₃ OD) δ (ppm): 1.27-1.40 (m, 2H), 1.62-1.71 (bd, 2H), 1.82-1.94 (m, 1H), 3.28-3.32 (d, 2H; partially hidden in the solvent), 3.38 (dt, 2H), 3.88-3.96 (bd, 2H), 4.97 (S, 2H), 5.46 (s, 2H), 7.05 (dd, 1H), 7.51 (dd, 1H), 7.57 (dd, 1H), 8.31 (d, 1H) , 9.20 (d, 1 H); MS (ESI): (M + H) ⁺ : 416.

一般的手順６に従い、１Ｈ−インダゾール−３−カルボン酸クロリド（１Ｈ−インダゾール−３−カルボン酸（１.１９ｇ、７.３ｍｍｏｌ）から一般的手順２を用いて製造した）、及び実施例５１ｂから得た３−アミノ−Ｎ−（シクロブチルメチル）ピリジン−２−カルボキサミド（０.５ｇ、２.４ｍｍｏｌ）を用い、精製後、標題の化合物（２０ｍｇ、収率：０.８％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.６８−１.８０（ｍ，２Ｈ），１.８１−１.９４（ｍ，２Ｈ），２.０３−２.１３（ｍ，２Ｈ），２.５３−２.６７（ｍ，１Ｈ），３.５１（ｄｄ，２Ｈ），７.２９（ｔ，１Ｈ），７.３９（ｔ，１Ｈ），７.４７（ｄｄ，１Ｈ），７.５５（ｄ，１Ｈ），８.２４（ｄｄ，１Ｈ），８.４１（ｄ，１Ｈ），８.５０（ｂｄ，１Ｈ），９.３０（ｄｄ，１Ｈ），１１.３７（ｓ，１Ｈ），１３.２６（ｓ，１Ｈ）；ＭＳ（ＥＳＩ）：（Ｍ＋Ｈ）⁺：３５０。 Example 64
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1H-indazole-3-carboxamide

According to general procedure 6, 1H-indazole-3-carboxylic acid chloride (prepared using general procedure 2 from 1H-indazole-3-carboxylic acid (1.19 g, 7.3 mmol)) and from Example 51b Using the obtained 3-amino-N- (cyclobutylmethyl) pyridine-2-carboxamide (0.5 g, 2.4 mmol), the title compound (20 mg, yield: 0.8%) was obtained after purification. .
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.68-1.80 (m, 2H), 1.81-1.94 (m, 2H), 2.03-2.13 (m, 2H) ), 2.53-2.67 (m, 1H), 3.51 (dd, 2H), 7.29 (t, 1H), 7.39 (t, 1H), 7.47 (dd, 1H) 7.55 (d, 1H), 8.24 (dd, 1H), 8.41 (d, 1H), 8.50 (bd, 1H), 9.30 (dd, 1H), 11.37 ( s, 1H), 13.26 (s, 1H); MS (ESI): (M + H) ⁺ : 350.

ＷＯ第２００５／１１５９８６号明細書、実施例１２９及び１３０に従って製造した、３−｛［４−（ブロモメチル）−１−ナフトイル］アミノ｝−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（２０ｍｇ、０.０４２ｍｍｏｌ）を、ＮａＨ（１.５ｍｇ、０.０６ｍｍｏｌ）及び（５−メチルイソオキサゾール−３−イル）メタノール（７ｍｇ、０.０６ｍｍｏｌ）のアセトニトリル（０.５ ｍｌ）溶液に加えた。反応溶液を水及びＤＣＭで希釈し、ＭｇＳＯ₄で乾燥し、濾過し、減圧下で濃縮した。粗製の生成物を分取型ＨＰＬＣで精製し、３−［（４−｛［（５−メチルイソオキサゾール−３−イル）メトキシ］メチル｝−１−ナフトイル）アミノ］−Ｎ−（テトラヒドロ−２Ｈ−ピラン−４−イルメチル）ピリジン−２−カルボキサミド（１.３ｍｇ、６.１％）を得た。
¹ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ₃）δ（ｐｐｍ）：１.３２−１.４４（ｍ，１Ｈ），１.６２−１.９０（ｍ，２Ｈ），２.４５（ｓ，３Ｈ），２.６１（ｓ，２Ｈ），３.２８−３.４０（ｍ，４Ｈ），３.９５−４.０２（ｍ，２Ｈ），４.６８（ｓ，２Ｈ），５.０４（ｓ；２Ｈ），７.５０−７.６３（ｍ，４Ｈ），７.８４−７.８９（ｍ，１Ｈ），８.０９−８.１５（ｍ，２Ｈ），８.２５−８.３０（ｍ，１Ｈ），８.５２−８.６０（ｍ，１Ｈ），９.３８−９.４３（ｍ，１Ｈ）。 Example 65
3-[(4-{[(5-Methylisoxazol-3-yl) methoxy] methyl} -1-naphthoyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide

3-{[4- (Bromomethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-, prepared according to WO 2005/115986, Examples 129 and 130 2-Carboxamide (20 mg, 0.042 mmol) was added to NaH (1.5 mg, 0.06 mmol) and (5-methylisoxazol-3-yl) methanol (7 mg, 0.06 mmol) in acetonitrile (0.5 ml). Added to the solution. The reaction solution was diluted with water and DCM, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 3-[(4-{[(5-methylisoxazol-3-yl) methoxy] methyl} -1-naphthoyl) amino] -N- (tetrahydro-2H -Pyran-4-ylmethyl) pyridine-2-carboxamide (1.3 mg, 6.1%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ (ppm): 1.32-1.44 (m, 1H), 1.62-1.90 (m, 2H), 2.45 (s, 3H), 2. 61 (s, 2H), 3.28-3.40 (m, 4H), 3.95-4.02 (m, 2H), 4.68 (s, 2H), 5.04 (s; 2H) , 7.50-7.63 (m, 4H), 7.84-7.89 (m, 1H), 8.09-8.15 (m, 2H), 8.25-8.30 (m, 1H), 8.52-8.60 (m, 1H), 9.38-9.43 (m, 1H).

Claims (55)

Formula (I):

Or a pharmaceutically acceptable salt, diastereomer, enantiomer, or mixture thereof.
In the above formula,
At least one of A ¹ and A ² is N, and if both are not N, the other is CH;
R ¹ is selected from hydrogen, cyano, halogen, hydroxy, NR ⁶ R ⁷ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-9 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy Wherein the C _2-6 alkenyl, C _2-6 alkynyl, C _1-9 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkoxy is optionally hydroxy, NR ^6a R ^7a , C Substituted with _3-6 cycloalkyl, aryl and heteroaryl;
R ² is selected from hydrogen, cyano, halogen, hydroxy, NR ⁶ R ⁷ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy Wherein the C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkoxy is optionally hydroxy, NR ^6a R ^7a , C Substituted with _3-6 cycloalkyl, aryl and heteroaryl;
R ³ is the following group:

Selected from
Wherein R ³ is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or hetero Substituted with aryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C ₃ Substituted with a saturated ring system consisting of 4 to 7 atoms selected from _-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl, heteroaryl, or C, N and O; Wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl or ring system is optionally substituted with C _1-4 alkyl; wherein the C _1-4 alkyl is optionally , NR ⁶ R ⁷ , aryl, hydroxy or Substituted with C _1-4 alkoxy;
R ⁴ is selected from hydrogen and C _1-6 alkyl;
R ⁵ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, heteroaryl and aryl; wherein the C _1-6 alkyl, C _{3 -6} cycloalkyl, heteroaryl or aryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy Substituted with aryl or heteroaryl;
n is selected from 0, 1, 2, 3, 4 and 5;
Or R ⁴ and R ⁵ together form a saturated, unsaturated or partially saturated ring system of 3 to 7 atoms selected from C, O and N;
Or R ⁴ and R ⁵ together form a saturated, unsaturated or partially saturated fused ring system of 7 to 13 atoms selected from C, O and N;
Wherein the ring system is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or Substituted with heteroaryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C Substituted by _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or heteroaryl;
R ⁶ , R ^6a , R ⁷ and R ^7a are independently of each other hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl. , C _2-6 alkynyl, aryl and heteroaryl; or R ^6a and R ^7a together form a saturated ring system of 4-7 atoms selected from C, O and N. And the ring system is optionally substituted with C _1-6 alkyl, C _1-6 alkoxy, halogen or hydroxy;
Wherein one or more carbon atoms of the alkyl or cycloalkyl group defined by R ¹ may be substituted with O, NH, C (O), SO or SO ₂ ; both O of, not adjacent to any other O or N; and, any of the SO or SO _2, not adjacent to any other SO or SO _2;
Here, one or more carbon atoms of the alkyl or cycloalkyl group defined by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ⁷ and R ^7a are O, NH, May be substituted with C (O) or SO ₂ , wherein neither N or O is adjacent to any other O or N;
Here, one or more carbon atoms of the alkyl or cycloalkyl group defined by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ⁷ and R ^7a are fluorine May be substituted with;
However,
R ³ is C _1-4 alkyl (where C _1-4 alkyl is heteroaryl, C _3-6 cycloalkyl, aryl, or a saturated ring consisting of 4 to 7 atoms selected from C, O and N) Substituted with a system, wherein the heteroaryl, C _3-6 cycloalkyl or aryl is further substituted with C _1-4 alkyl or halogen, wherein the C _1-4 alkyl is optionally NR ⁶ R ^7, aryl, substituted with hydroxy or C _1-4 alkoxy, wherein the ring system is optionally substituted by C _1-4 alkyl, wherein said C _1-4 alkyl is optionally , Substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy);
Or, R ³ is the following group:

(Wherein these groups are optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl Or substituted with heteroaryl)
If not selected from
R ² is hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _1-6 haloalkyl, C _2-6 In the case of haloalkenyl or NR ⁶ R ⁷ , R ¹ is simultaneously hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy, C _2-6 alkenyl , C _1-6 haloalkyl, C _2-6 haloalkenyl, or NR ⁶ R ⁷ . Formula (I):

Or a pharmaceutically acceptable salt, diastereomer, enantiomer, or mixture thereof.
In the above formula,
At least one of A ¹ and A ² is N, and if both are not N, the other is CH;
R ¹ is selected from hydrogen, cyano, halogen, hydroxy, NR ⁶ R ⁷ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy Wherein the C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkoxy is optionally hydroxy, NR ^6a R ^7a , C Substituted with _3-6 cycloalkyl, aryl or heteroaryl;
R ² is selected from hydrogen, cyano, halogen, hydroxy, NR ⁶ R ⁷ , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy Wherein the C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkoxy is optionally hydroxy, NR ^6a R ^7a , C Substituted with _3-6 cycloalkyl, aryl or heteroaryl;
R ³ represents the following group:

Selected from
Wherein R ³ is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or hetero Substituted with aryl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C ₃ Substituted with _-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or heteroaryl; wherein said C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally Substituted with C _1-4 alkyl; wherein the C _1-4 alkyl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy;
R ⁴ is selected from hydrogen and C _1-6 alkyl;
R ⁵ is selected from C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, heteroaryl and aryl; wherein the C _1-6 alkyl, C _{3 -6} cycloalkyl, heteroaryl or aryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy Substituted with aryl or heteroaryl;
n is selected from 0, 1, 2, 3, 4 and 5;
Or, R ⁴ and R ⁵ come together, C, saturated consisting 3-7 groups selected from O and N, unsaturated, or partially saturated ring system;
Or R ⁴ and R ⁵ together form a 7-13 saturated, unsaturated or partially saturated fused ring system selected from C, O and N;
Wherein the ring system is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or Substituted with heteroaryl; and wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl Substituted with C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or heteroaryl;
R ⁶ , R ^6a , R ⁷ and R ^7a are independently of each other hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl. , C _2-6 alkynyl, aryl and heteroaryl;
Wherein one or more carbon atoms of each of the alkyl or cycloalkyl groups defined by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ⁷ and R ^7a are , O, NH, C (O) or SO ₂ may be substituted;
Wherein one or more carbon atoms of each of the alkyl or cycloalkyl groups defined by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ⁷ and R ^7a are May be substituted with fluorine; and
R ³ is C _1-4 alkyl (wherein the C _1-4 alkyl is substituted with heteroaryl, C _3-6 cycloalkyl or aryl, which is further substituted with C _1-4 alkyl, where the C _{1 -4} alkyl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy);
Or, R ³ is the following group:

If not selected from
R ² is hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _1-6 haloalkyl, C _2-6 In the case of haloalkenyl or NR ⁶ R ⁷ , R ¹ is simultaneously hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy, C _2-6 alkenyl , C _1-6 haloalkyl, C _2-6 haloalkenyl, or NR ⁶ R ⁷ . The compound according to claim 1 or ^{2, wherein} A ¹ and A ² are N. The compound according to claim 1 or ² , wherein A ¹ is N and A ² is CH. The compound according to any one of claims 1 to 4, wherein R ⁴ is hydrogen.   6. The compound according to any one of claims 1 to 5, wherein n is 1. R ² is hydrogen A compound according to any one of claims 1-6. R ² is, optionally, hydroxy, NR ^6a R ^7a, a C _3-6 cycloalkyl, C _1-6 alkyl substituted with aryl or heteroaryl, according to any one of claims 1 to 6 Compound. The compound according to any one of claims 1 to 8, wherein R ¹ is hydrogen. R ¹ is selected from cyano, halogen, NR ⁶ R ⁷ , C _1-9 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy, wherein the C _1-9 alkyl, C _3-6 The cycloalkyl or C _1-6 haloalkoxy is optionally substituted with hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or heteroaryl. Compound described in 1. R ¹ is selected from cyano, halogen, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 haloalkoxy, wherein the C _1-6 alkyl, C _3-6 The cycloalkyl or C _1-6 haloalkoxy is optionally substituted with hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or heteroaryl. Compound. _11. A compound according to claim 10, wherein R ^{< 1} _{> is} C1-9 alkyl, optionally substituted with hydroxy, NR <^6a> R ^<7a> , _C3-6 cycloalkyl, aryl or heteroaryl. Optionally R ¹ is hydroxy, NR ^6a R ^7a, a C _3-6 cycloalkyl, C _1-6 alkyl substituted with aryl or heteroaryl, A compound according to claim 11. One carbon atom of the alkyl as defined by R ¹ is substituted with at least one fluorine compound according to claim 12 or 13. At least one carbon atom of the alkyl group defined by R ¹ is substituted with O, A compound according to claim 12 or 13. At least one carbon atom of the alkyl group defined by R ¹ is, NH, C (O), is replaced by SO or SO _2, A compound according to claim 12 or 13. R ¹ is C _3-9 alkyl, and at least two carbon atoms in the alkyl group defined by R ¹ is substituted with O, The compound of claim 12. 13. A compound according to claim 12, wherein R _< ¹ _> is _C3-6 alkyl and at least two carbon atoms of the alkyl group defined by R < ¹ > are substituted with O. At least one carbon atom of the alkyl group defined by R ¹ is substituted with C (O), A compound according to claim 12 or 13. R ⁵ is C _3-6 cycloalkyl, A compound according to any one of claims 1 to 19. R ⁵ is C ₄ cycloalkyl or C ₆ cycloalkyl, A compound according to claim 20. R ⁵ is cyclobutyl or cyclohexyl or tetrahydropyran compound according to claim 21. R ³ is the following group:

Wherein R ³ is optionally substituted with halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy, wherein the C 3 _1-6 alkyl or C _3-6 cycloalkyl is optionally halogen, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, aryl, heteroaryl, or C, Substituted with a saturated ring system of 4 to 7 atoms selected from N and O; wherein said C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl or ring system is Accordingly, by substituted with C _1-4 alkyl; and wherein said C _1-4 alkyl is optionally, NR ⁶ R ^7, aryl, optionally substituted with hydroxy or C _1-4 alkoxy, claim 1 or 3 The compound of any one of -22. R ³ is:

Wherein R ³ is optionally substituted with halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy, wherein the C 3 _1-6 alkyl or C _3-6 cycloalkyl is optionally halogen, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, aryl, heteroaryl, or C, Substituted by a saturated ring system consisting of 4 to 7 atoms selected from N and O; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl or ring system is by is substituted with C _1-4 alkyl, wherein optionally the C _1-4 alkyl, NR ⁶ R ^7, aryl, optionally substituted with hydroxy or C _1-4 alkoxy, a compound according to claim 23 . R ³ is the following group:

Wherein R ³ is optionally substituted with halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy; _1-6 alkyl or C _3-6 cycloalkyl is optionally substituted with halogen, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy aryl or heteroaryl; Wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally substituted with C _1-4 alkyl; wherein the C _1-4 alkyl is optionally NR ⁶ R ^7, aryl, optionally substituted with hydroxy or C _1-4 alkoxy, a compound according to any one of claims 2 to 22. R ³ is naphthyl optionally substituted with halogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy, wherein the C _1-6 Alkyl or C _3-6 cycloalkyl is optionally halogen, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, aryl, heteroaryl, or C, N and O Substituted with a saturated ring system of 4 to 7 atoms selected from: wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl, heteroaryl or ring system is optionally C substituted with _1-4 alkyl; and, wherein the C _1-4 alkyl is optionally, NR ⁶ R ^7, aryl, optionally substituted with hydroxy or C _1-4 alkoxy, any of claims 1 to 25 2. The compound according to item 1. R ³ is naphthyl substituted by C _1-6 alkyl, wherein said C _1-6 alkyl is substituted with a heteroaryl; and wherein the heteroaryl is optionally, C _1-4 alkyl 27. The compound of claim 26, wherein said C _1-4 alkyl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy. C _1-6 alkyl is methyl A compound according to claim 27.   29. A compound according to claim 27 or 28 wherein heteroaryl is 1,2,3-triazolyl. R ³ is the following group:

Wherein R ³ is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy 10. A compound according to claim 9, substituted by aryl, heteroaryl. R ³ is naphthyl substituted with methyl, wherein the methyl is substituted with 1,2,3-triazolyl; wherein the 1,2,3-triazolyl is substituted with C _1-4 alkyl And wherein the C _1-4 alkyl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy, or C _1-4 alkoxy. R ¹ is hydrogen or C _1-9 alkyl, wherein the C _1-9 alkyl is optionally substituted with hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or heteroaryl;
R ² is hydrogen or C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted with hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or heteroaryl;
R ³ represents the following group:

Is selected from, where, R ³ is substituted with C _1-6 alkyl, wherein said C _1-6 alkyl is optionally heteroaryl, or 4-7 to C, selected from N and O And wherein the heteroaryl or ring system is optionally substituted with C _1-4 alkyl; wherein the C _1-4 alkyl is optionally substituted with a saturated ring system consisting of Substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy;
R ⁴ is hydrogen;
R ⁵ is C _3-6 cycloalkyl;
n is 1;
R ⁶ , R ^6a , R ⁷ and R ^7a are independently of one another selected from hydrogen and C _1-6 alkyl; or
R ^6a and R ^7a together form a saturated ring system consisting of 4 to 7 atoms selected from C, O and N; the ring system is optionally C _1-6 alkyl, Substituted with C _1-6 alkoxy, halogen or hydroxy;
Wherein one or more carbon atoms of each alkyl or cycloalkyl group defined by R ¹ may be substituted with O, NH, C (O), SO or SO ₂ , where any of O or N, not adjacent to any other O or N, where none of the SO or SO _2, not adjacent to any other SO or SO _2;
Wherein one or more carbon atoms of each of the alkyl or cycloalkyl groups defined by R ² , R ³ and R ⁵ may be substituted with O, NH, C (O) or SO _2. Where neither O or N is adjacent to any other O or N;
Wherein one or more carbon atoms of each of the alkyl or cycloalkyl groups defined by R ¹ and R ³ may be substituted with fluorine;
However,
R ³ is C _1-4 alkyl (where C _1-4 alkyl is heteroaryl, C _3-6 cycloalkyl, aryl, or a saturated ring consisting of 4 to 7 atoms selected from C, O and N) Substituted with a system, wherein the heteroaryl, C _3-6 cycloalkyl or aryl is further substituted with C _1-4 alkyl or halogen, wherein the C _1-4 alkyl is optionally NR ⁶ R ^7, aryl, substituted with hydroxy or C _1-4 alkoxy, wherein the ring system is optionally substituted by C _1-4 alkyl, wherein said C _1-4 alkyl is optionally , Substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy);
Or, R ³ is the following group:

Where R ³ is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or Substituted with heteroaryl)
If not selected from
R ² is hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy, C _2-6 alkenyl, C _1-6 haloalkyl, C _2-6 In the case of haloalkenyl or NR ⁶ R ⁷ , R ¹ is simultaneously hydrogen, halogen, cyano, acetylamino, hydroxy, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 haloalkoxy, C _2-6 alkenyl , C _1-6 haloalkyl, C _2-6 haloalkenyl or NR ⁶ R ⁷ ;
2. The compound of claim 1, or a pharmaceutically acceptable salt, diastereomer, enantiomer, or mixture thereof. A ¹ is N, A ² is N, A compound according to claim 32. A ¹ is N, A ² is CH, and A compound according to claim 32. R ¹ is selected from hydrogen or C _1-6 alkyl, which C _1-6 alkyl is optionally substituted with hydroxy, NR ^6a R ^7a , C _3-6 cycloalkyl, aryl or heteroaryl;
R ² is hydrogen;
R ³ is optionally substituted with halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or heteroaryl Wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is optionally halogen, cyano, nitro, NR ⁶ R ⁷ , C _1-6 alkyl, C Substituted with _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, aryl or heteroaryl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, aryl or heteroaryl is Optionally further substituted with C _1-4 alkyl; wherein the C _1-4 alkyl is optionally substituted with NR ⁶ R ⁷ , aryl, hydroxy or C _1-4 alkoxy;
R ⁴ is hydrogen;
R ⁵ is C _3-6 cycloalkyl;
R ⁶ is hydrogen or C _1-4 alkyl;
R ⁷ is hydrogen or C _1-4 alkyl;
R ^6a is hydrogen or C _1-4 alkyl; and
R ^7a is hydrogen or C _1-4 alkyl;
The compound according to any one of claims 2 to 4. A compound selected from the following compounds:
[(6-{[(cyclohexylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) oxy ] Methyl acetate;
[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) Oxy] methyl acetate;
[(6-{[(Cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl) Oxy] acetic acid;
6- (2-Amino-2-oxoethoxy) -N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-carboxamide;
N- (cyclobutylmethyl) -6- [2- (methylamino) -2-oxoethoxy] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] Amino} pyridine-2-carboxamide;
N- (cyclobutylmethyl) -6- [2- (dimethylamino) -2-oxoethoxy] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] Amino} pyridine-2-carboxamide;
N- (cyclobutylmethyl) -6- {2-[(2-hydroxyethyl) amino] -2-oxoethoxy} -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide;
Ethanesulfonic acid 6-{[(cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl ;
3,3,3-trifluoropropane-1-sulfonic acid 6-{[(cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl)- 1-naphthoyl] amino} pyridin-2-yl;
3,3,3-trifluoropropane-1-sulfonic acid 6-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazole -1-ylmethyl) -1-naphthoyl] amino} pyridin-2-yl;
Acetic acid 6-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-yl;
N- (cyclobutylmethyl) -6- (2-hydroxyethoxy) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide ;
N- (cyclobutylmethyl) -6- [2- (2-hydroxyethoxy) ethoxy] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} Pyridine-2-carboxamide;
6- (Benzyloxy) -N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-carboxamide;
3-Benzyl-1-[(4-{[(6- (benzyloxy) -2-{[(tetrahydro-2H-pyran-4-ylmethyl) amino] carbonyl} pyridin-3-yl) amino] carbonyl}- 1-naphthyl) methyl] -1H-1,2,3-triazole-3-ium;
N- (cyclobutylmethyl) -6- (pyridin-2-ylmethoxy) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2- Carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[5- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[5- (1-hydroxyethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine- 2-carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[4- (1-hydroxyethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine- 2-carboxamide;
3-[(4-{[5- (aminocarbonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] -N- (cyclobutylmethyl) pyridine-2- Carboxamide;
3-[(4-{[4- (Aminocarbonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] -N- (cyclobutylmethyl) pyridine-2- Carboxamide;
6- (aminomethyl) -N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide;
N- (cyclobutylmethyl) -6- (hydroxymethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide;
N- (cyclobutylmethyl) -6-{[(methylsulfonyl) amino] methyl} -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine -2-carboxamide;
6-{[(cyclobutylmethyl) amino] carbonyl} -5-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} methyl pyridine-2-carboxylate;
N ^2- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2,6-dicarboxamide; and N- ( Cyclobutylmethyl) -6-methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1- Naphthoyl] amino} pyrazine-2-carboxamide. A compound selected from the following compounds:
6- (2-morpholin-4-yl-2-oxoethoxy) -3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2- Carboxylic acid cyclobutylmethyl-amide;
{6- (Cyclobutylmethyl-carbamoyl) -5-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridin-2-yloxy} -acetic acid 2, 2-dimethylpropyl ester;
{6- (Cyclobutylmethyl-carbamoyl) -5-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridin-2-yloxy} -acetic acid isopropyl ester ;
6-hydroxycarbamoylmethoxy-3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid cyclobutylmethyl-amide;
6- (methoxycarbamoyl-methoxy) -3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid cyclobutylmethyl-amide;
{5-[(4-Methyl-naphthalene-1-carbonyl) -amino] -6-[(tetrahydro-pyran-4-ylmethyl) -carbamoyl] -pyridin-2-yloxy} -acetic acid methyl ester;
6-carbamoylmethoxy-3-[(4-methyl-naphthalen-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
{5-[(4-Methyl-naphthalene-1-carbonyl) -amino] -6- (tetrahydro-pyran-4-ylmethyl) -carbamoyl] -pyridin-2-yloxy} -acetic acid;
6- (2-hydroxy-ethoxy) -3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6- (2-hydroxy-ethoxy) -3-[(4-methoxymethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-methanesulfonyl-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-methanesulfinyl-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6- [2- (2-hydroxy-ethoxy) -ethoxy] -3-[(4- [1,2,3] triazol-1-ylmethyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid Acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-methoxy-3-({4-[(4-methylpiperazin-1-yl) methyl] -1-naphthoyl} amino) -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
6-methoxy-3-{[4- (morpholin-4-ylmethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
6-[(ethylamino) sulfonyl] -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
6- (benzylsulfonyl) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
6- (benzylsulfonyl) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
3,3,3-trifluoropropane-1-sulfonic acid 6-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] -5-{[4- (1H-1,2,3-triazole-1- Ylmethyl) -1-naphthoyl] amino} pyrazin-2-yl;
N- (cyclobutylmethyl) -3-{[4-({5-[(dimethylamino) methyl] -1H-1,2,3-triazol-1-yl} methyl) -1-naphthoyl] amino} pyridine -2-carboxamide;
N- (cyclobutylmethyl) -3-{[4-({4-[(dimethylamino) methyl] -1H-1,2,3-triazol-1-yl} methyl) -1-naphthoyl] amino} pyridine -2-carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[4- (trifluoromethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2 A carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[5- (phenylsulfonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide;
N- (cyclobutylmethyl) -3-[(4-{[4- (phenylsulfonyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] pyridine-2- Carboxamide;
N- (cyclobutylmethyl) -3-({4-[(4-fluoro-1H-1,2,3-triazol-1-yl) methyl] -1-naphthoyl} amino) pyridine-2-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1-methyl-1H-indole-3-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1-methyl-1H-indole-2-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1H-indole-3-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] -4-methoxyphenyl} quinoline-4-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] -6-methoxypyridin-3-yl} -1-methyl-1H-indazole-3-carboxamide;
3-[(1-benzothien-3-yl-carbonyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
3-[(5,6,7,8-tetrahydronaphthalen-1-ylcarbonyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
N- {2-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1H-indazole-3-carboxamide;
N- {2-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1H-indole-3-carboxamide;
1-methyl-N- {2-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1H-indole-3-carboxamide;
N- {2-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1,3-benzothiazole-6-carboxamide;
N- {2-[(tetrahydro-2H-pyran-4-ylmethyl) carbamoyl] pyridin-3-yl} -1,6-naphthyridine-5-carboxamide;
3-{[(6-fluoro-4H-1,3-benzodioxin-8-yl) carbonyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
N- {2-[(cyclobutylmethyl) carbamoyl] pyridin-3-yl} -1H-indazole-3-carboxamide; and 3-[(4-{[(5-methylisoxazol-3-yl) methoxy] Methyl} -1-naphthoyl) amino] -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide.   38. A pharmaceutical composition comprising a compound according to any one of claims 1-37 as an active ingredient and a pharmaceutically acceptable carrier or excipient.   38. A compound according to any one of claims 1 to 37 for use in therapy.   38. Use of a compound according to any one of claims 1 to 37 for the manufacture of a medicament for treating gastroesophageal reflux disease (GERD).   38. Use of a compound according to any one of claims 1 to 37 for the manufacture of a medicament for preventing backflow.   38. Use of a compound according to any one of claims 1 to 37 for the manufacture of a medicament that inhibits transient lower esophageal sphincter relaxation (TLESR).   38. Use of a compound according to any one of claims 1-37 for the manufacture of a medicament for treating functional gastrointestinal disorders.   38. Use of a compound according to any one of claims 1 to 37 for the manufacture of a medicament for treating functional dyspepsia.   38. Use of a compound according to any one of claims 1 to 37 for the manufacture of a medicament for treating irritable bowel syndrome (IBS).   38. Use of a compound according to any one of claims 1 to 37 for the manufacture of a medicament for treating pain.   38. A method of treating gastroesophageal reflux disease (GERD), comprising administering to a subject in need thereof a pharmaceutically and pharmacologically effective amount of a compound according to any one of claims 1-37. Method of treatment.   38. A method of preventing reflux, comprising administering to a subject in need thereof a pharmaceutically and pharmacologically effective amount of the compound of any one of claims 1-37.   38. A method for inhibiting transient lower esophageal sphincter relaxation (TLESR), wherein the pharmacologically and pharmacologically effective amount of the compound according to any one of claims 1 to 37 is a subject in need of inhibition. Method of treatment.   38. A method of treating functional gastrointestinal disorders, comprising administering to a subject in need thereof a pharmaceutically and pharmacologically effective amount of a compound according to any one of claims 1-37.   38. A method of treating functional dyspepsia, comprising administering a pharmaceutically and pharmacologically effective amount of the compound of any one of claims 1-37 to a subject in need thereof.   38. A method of treating irritable bowel syndrome (IBS), comprising administering to a subject in need thereof a pharmaceutically and pharmacologically effective amount of a compound according to any one of claims 1-37. Method of treatment.   38. A method of treating pain, comprising administering to a subject in need thereof a pharmaceutically and pharmacologically effective amount of the compound of any one of claims 1-37. A compound selected from the following compounds:
N- (cyclobutylmethyl) -6-hydroxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide;
6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2- Carboxamide;
3-[(4-{[5- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] methyl pyridine-2-carboxylate;
3-[(4-{[4- (methoxymethyl) -1H-1,2,3-triazol-1-yl] methyl} -1-naphthoyl) amino] methyl pyridine-2-carboxylate;
3-{[4- (azidomethyl) -1-naphthoyl] amino} methyl pyridine-2-carboxylate;
6-cyano-N- (cyclobutylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyridine-2-carboxamide;
Methyl 6-cyano-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate;
Methyl 6-chloro-3-[(4-methyl-1-naphthoyl) amino] pyridine-2-carboxylate;
6-methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine -2-carboxylic acid;
6-methoxy-5-[(tetrahydro-2H-pyran-4-ylmethyl) amino] -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine Methyl-2-carboxylate;
Methyl 5-chloro-6-methoxy-3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2-carboxylate;
Methyl 5-chloro-6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyrazine-2-carboxylate;
Methyl 6-methoxy-3-[(4-methyl-1-naphthoyl) amino] pyrazine-2-carboxylate;
3-amino-6-methoxypyrazine-2-carboxylic acid;
Methyl 3-amino-6-methoxypyrazine-2-carboxylate;
6-bromo-3- (3-chlorophenyl) pteridine-2,4 (1H, 3H) -dione;
3-{[4- (bromomethyl) -1-naphthoyl] amino} methyl pyridine-2-carboxylate;
Methyl 3-amino-6-bromopyrazine-2-carboxylate;
6-hydroxy-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-hydroxy-N- (tetrahydro-2H-pyran-4-ylmethyl) -3-{[4- (1H-1,2,3-triazol-1-ylmethyl) -1-naphthoyl] amino} pyrazine-2- Carboxamide;
3-[(4-methyl-naphthalene-1-carbonyl) -amino] -6-methylsulfanyl-pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-chloro-3-[(4-methyl-naphthalene-1-carbonyl) -amino] -pyridine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl) -amide;
6-chloro-3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
3-{[4- (bromomethyl) -1-naphthoyl] amino} -6-methoxy-N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
6- (benzylthio) -3-{[4- (methoxymethyl) -1-naphthoyl] amino} -N- (tetrahydro-2H-pyran-4-ylmethyl) pyridine-2-carboxamide;
Methyl 5-methoxy-2-[(quinolin-4-ylcarbonyl) amino] benzoate; and 6-methoxy-3-{[(1-methyl-1H-indazol-3-yl) carbonyl] amino} pyridine-2 -Methyl carboxylate.   58. Use of a compound according to claim 54 in a process for producing a compound according to any one of claims 1-37.